HRP970426A2 - Fluorine containing 1,4-disubstituted piperidine derivatives - Google Patents

Description

The field of invention

This invention relates to new derivatives of 1,4-disubstituted piperidine containing fluorine, a process for their preparation, pharmaceuticals containing or containing them and their use as drugs, especially for the treatment and prevention of various diseases of the respiratory, urinary and digestive systems.

Previous knowledge

Antagonism of muscarinic receptors is known to cause bronchodilation, gastrointestinal hypanakinesis, decreased gastric secretion, dry mouth, mydriasis, decreased bladder contraction, hypohidrosis, tachycardia, and the like ["Basic and Clinical Pharmacology", 4th edition, APPLETON & LANGE, p. 83-92 (1989); Drug News & Perspective. 5(6), p. 345-352 (1992)].

It has become clear through recent studies that there are at least three subtypes of muscarinic receptors; M1 receptors mainly present in the brain, M2 receptors mainly in the heart and M3 receptors, on smooth muscles and glandular tissues. All of the large number of compounds known to show antagonism towards muscarinic receptors indiscriminately antagonize three subtypes of muscarinic receptors. Accordingly, attempts to use these compounds as therapeutic and prophylactic agents for diseases of the respiratory system have caused unwanted side effects such as dry mouth, vomiting and mydriasis. Additionally, particularly serious side effects are a problem related to the central nervous system, such as dementia, attributed to M1 receptors and those related to the heart, such as tachycardia related to M2 receptors, and their solution is highly sought after.

We have discovered, as a drug according to the claims, derivatives of 1,4-disubstituted piperidine (see: PCT WO96/33973). However, the creation of even better medicines is sought.

One object of the present invention is to create an even better drug than said known compounds, thereby providing pharmaceuticals that exhibit highly selective antagonism towards M3 receptors and reduce adverse side effects and therefore provide safe and effective pharmaceuticals for the treatment and prevention of diseases associated with muscarinic M3 receptors, for example such respiratory diseases as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable stomach syndrome, ulcerative colitis, diverticulitis and contraction of the smooth muscles of the digestive system accompanied by pain; urinary disorders such as urinary incontinence and frequency of neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, inconstant bladder, cystospasm and chronic cystitis; and motion sickness.

The discovery of an invention

According to the present invention, new fluorine-containing 1,4-disubstituted piperidine derivatives of the general formula [I] are provided.

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and their pharmaceutically acceptable salts, where:

Ar represents an aryl group or a heteroaryl group having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (any 1 to 3 hydrogen atoms on the ring of said aryl or heteroaryl group can be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino and lower alkylamino);

R1 represents C3-C6 cycloalkyl any of the 1-4 hydrogen atoms may be substituted with fluorine atom(s);

R2 represents a C3-C15 saturated and unsaturated aliphatic hydrocarbon group of which any of 1 to 6 hydrogen atoms may be substituted with a fluorine atom(s), an aralkyl, arylalkeny, heteroarylalkyl or heteroarylalkenyl group having 1 to 2 hetero atoms selected from the group consisting of consists of nitrogen, oxygen and sulfur (optionally any of 1 to 3 hydrogen atoms on the ring in said aralkyl, arylalkenyl, heteroarylalkyl and heteroarylalkenyl group can be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen , lower alkoxy, amino or lower alkylamino); and

X is O or NH,

ensuring that at least one of R1 and R2 contains one or more fluorine atoms.

The compounds of the above formula [I] provided by the present invention have not only a strong and selective activity for muscarinic M3 receptors, but also a small side effect. Furthermore, they show excellent oral activity, duration of action and pharmacokinetics. This is why they are very useful in the treatment or prophylaxis of diseases such as respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable stomach syndrome, ulcerative colitis, diverticulitis and contraction of the smooth muscles of the digestive system accompanied by pain; urinary disorders such as urinary incontinence and frequency of neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, inconstant bladder, cystospasm and chronic cystitis; and motion sickness.

Hereinafter, the meaning of the technical terms used in the present specification is clarified and the invention is explained in further detail.

"Aryl group (any 1 to 3 hydrogen atoms on the ring of said aryl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino)" means substituted or unsubstituted C6 -C11 aryl group, examples of which include an unsubstituted phenyl group, a naphthyl group or those containing the above named substituent(s).

As examples of a "heteroaryl group having 1-2 atoms selected from the group consisting of nitrogen, oxygen and sulfur (any 1 to 3 hydrogen atoms on the ring of said aryl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro , lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino)", unsubstituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 2-thienyl, 3-thienyl, 1-imidazolyl, 2 -imidazolium, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl , 4-pyridazinyl, 2-quinolinyl, 2-benzothienyl and 2-indolyl group; and those substituted with the above-named substituents may be listed.

Also examples of "C3-C6 cycloalkyl whose 1-4 hydrogen atoms may be substituted with fluorine atom(s)" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-fluorocyclopropyl, l-fluorocyclobutyl, 1-fluorocyclopentyl, 1-fluorocyclohexyl, 2 -fluorocyclopropyl, 2-fluorocyclobutyl, 2-fluorocyclopentyl, 2-fluorocyclohexyl, 3-fluorocyclobutyl, 3-fluorocyclopentyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 2,2-difluorocyclopropyl, 2,2-difluorocyclobutyl, 2,2-difluorocyclopentyl, 2,2-difluorocyclohexyl, 3,3-difluorocyclobutyl, 3,3-difluorocyclopentyl, 3,3-difluorocyclohexyl, 4,4-difluoro cyclohexyl3,3,4,4,-tetrafluorocyclopentyl, 3,3,4,4-tetrafluorocyclohexyl, 2,3-difluorocyclobutyl, 2,3-difluorocyclopentyl, 3,4-difluorocyclopentyl, 2,3-difluorocyclohexyl, 3,4-difluorocyclohexyl, 2,2,3,3-tertrafluorocyclobutyl and 2,2,3,3-tetrafluorocyclopentyl groups.

Examples of "C5-C15 saturated or unsaturated aphatic hydrocarbon groups of which any 1 to 6 hydrogen atoms may be substituted with fluorine atom(s)" include C5-C15 straight chain or branched alkyl, alkenyl, alkynyl, cycloalkylidenealkyl; cycloalkylalkyl, cycloalkylalkenyl or cycloaholalkynyl wherein the hydrogen atom(s) on the cycloalkanyl ring may optionally be substituted with lower alkyl; and cycloalkenylalkyl or cycloalkenylalkenyl wherein the hydrogen atom(s) on the cycloalkyl ring may optionally be substituted with lower alkyl; and those having any 1 to 6 hydrogen atoms substituted with a fluorine atom.

Certain examples of such aliphatic hydrocarbon groups include:

unsubstituted or fluorine-substituted alkyl groups such as 2-methylbutyl, 3-methylbutyl, pentyl, neopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- methylhexyl, 2,4-dimethylpentyl, 2-ethylhexyl, 4,5-dimethylhexyl, 4,4-dimethylpentyl, heptyl, 4-methylheptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3-fluoromethylbutyl, 1-fluoropentyl, 4-fluoropentyl, 5-fluoropentyl, 1,1-difluoropentyl, 4,4-difluoropentyl, 5,5,5-trifluoropentyl, 1,1,4,4,-tetrafluoropentyl, 1,1,5,5 ,5,-pentafluoropentyl, 1-fluorohexyl, 5-fluorohexyl, 6-fluorohexyl, 1,1-difluorohexyl, 5,5-difluorohexyl, 6,6,6-trifluorohexyl, 1,1,5,5-tetrafluorohexyl, 1, 1,6,6,6-penta fluorohexyl, 1-fluoro-4-methylpentyl, 2-fluoro-4-methylpentyl, 3-fluoro-4-methylpentyl, 4-fluoro-4-methylpentyl, 4-fluoro methylpentyl, 1, 1-difluoro-4-methylpentyl, 4-trifluoromethylpentyl, 5,5,5,-trifluoro-4-trifluoromethylpentyl, 1,1-difluoro-4-tri fluoromethylpent 1,1,1,5-trifluoro-4-methylpentyl, 1-fluoro-4-methylhexyl, 4-fluoro-4-methyldihexyl, 5-fluoro-4-methylhexyl, 6-fluoro-4-methylhexyl, 1,1- difluoro-4-methylhexyl, 5,5-difluoro-4-methylhexyl, 4-trifluoromethylhexyl, 6,6,6-trifluoro-4-methylhexyl, 6,6,6-trifluoro-4-trifluoromethyl]hexyl, 1,1- difluoro-4-trifluoromethylhexyl and 1,1-difluoro-6,6,6-trifluoro-4-methylhexyl;

unsubstituted or fluorine-substituted alkenyl groups such as 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-2- pentenyl, 4-methyl-3-pentenyl, 4-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 4-methyl-2-hexenyl, 4-methyl-3-hexenyl, 4-methyl- 4-hexenyl, 5-methyl-2-hexenyl, 5-methyl-3-hexenyl, 5-methyl-4-hexenyl, 5-methyl-2-heptenyl, 5-methyl-3-heptenyl, 5-methyl-4- heptenyl, 5-methyl-5-heptenyl, 3,4-dunethyl-2-pentenyl, 3,4-dimethyl-3-pentenyl, 4,5-dimethyl-2-hexenyl, 4,5-dimethyl-3-hexenyl, 4,5-dunethyl-4-hexenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, l-fluoro-4-methyl-3-pentenyl, 2-fluoro-4-methyl-3-pentenyl, (E)-4-fluoromethyl-3-pentenyl, (Z)-4-fluoromethyl-3-pentenyl, 1,1-difluoro-4-methyl-3-pentenyl, 2,2-difluoro-4-methyl-3- pentenyl, (E)-4-trifluoromethyl-3-pentenyl,, (Z)-4-trifluoromethyl-3-pentenyl, (E)-1,1-difluoro-4-trifluoromethyl-3-pentenyl, (Z)-1 ,1-difluoro-4-trifluoromethyl-3-p entenyl, 5,5,5-trifluoro-4-trifluoromethyl-3-pentenyl, 1-fluoro-4-methyl-2-pentenyl, 4-fluoro-4-methyl-2-pentenyl, 4-fluoromethyl-2-pentenyl, 1,1-difluoro-4-methyl-2-pentenyl, 4-trifluoromethyl-2-pentenyl, 4-fluoro-1,1-difluoro-4-methyl-2-pentenyl, 1,1-difluoro-4-trifluoromethyl- 2-pentenyl, l-fluoro-4-methyl-4-pentenyl, 2-fluoro-4-methyl-4-pentenyl, 3-fluoro-4-methyl-4-pentenyl, 4-fluoromethyl-4-pentenyl, 1, 1-difluoro-4-methyl-4-pentenyl, 2,2-difluoro-4-methyl-4-pentenyl, 3,3-difluoro-4-methyl-4-pentenyl, 4-trifluoromethyl-4-pentenyl, 1, 1-difluoro-4-trifluoromethyl-4-pentenyl, 1,1,3,3-tetrafluoro-4-methyl-4-pentenyl, 1-fluoro-4-methyl-3-hexenyl, 2-fluoro-4-methyl- 3-hexenyl, 4-fluoromethyl-3-hexenyl, 6-fluoro-4-methyl-3-hexenyl, 4-trifluoromethyl-3-hexenyl, 1,1-difluoro-4-methyl-3-hexenyl, 2,2- difluoro-4-methyl-3-hexenyl, 4-trifluoromethyl-3-hexenyl, 5,5-difluoromethyl-3-hexenyl, 6,6,6-trifluoro-4-methyl-3-hexenyl, 1,1-difluoro- 4-trifluoromethyl-3-hexenyl and 6,6,6-trifluoro-4-trifluoromethyl-3-hexenyl; 2-pentynyl, 3-pentynyl, 4-pentynyl, 4-methyl-2-pentynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl and pentadecynyl, and those alkynyl groups in which optionally any of l to 6 hydrogen atoms substituted with fluorine atom(s);

unsubstituted and fluorine-substituted cycloalkylalkyl groups in which any of the hydrogen atoms on the cycloalkyl ring may be substituted with lower alkyl, such as cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclopropylhexyl, cyclopropylheptyl,, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpentyl, cyclopentylmethyl . -ethylcyclopentylmethyl, 3-ethylcyclopentylmethyl, 2-cyclopentylethyl, 2-(l-methylcyclopentyl)ethyl, 2-(2-methylcyclopentyl)ethyl, 2-(3-methylcyclopentyl)ethyl, 2-(l-ethylcyclopentyl)ethyl, 2 -(2-ethylcyclopentyl)ethyl, 2-(3-ethylcyclopentyl)ethyl, 1- methylcyclohexylmethyl, 2-methylcyclohexylmethyl, 3-methylcyclohexylmethyl, 4-methylcyclohexylmethyl, 1-ethylcyclohexylmethyl, 2-ethylcyclohexylmethyl, 3-ethylcyclohexylmethyl, 4-ethylcyclohexylmethyl, cyclohexylethyl, 2-(l-methylcyclohexyl)ethyl, 2-(2-methylcyclohexyl)ethyl, 2-(3-methylcyclohexyl)ethyl, 2-(4-methylcyclohexyl)ethyl, 2-(1-ethylcyclohexyl)ethyl, 2-(2-ethylcyclohexyl)ethyl, 2-(3-ethylcyclohexyl)ethyl, 2-(4- ethylcyclohexyl)ethyl, 1-methylcycloheptylmethyl, 2-methylcycloheptylmethyl, 3-methylcycloheptylmethyl, 4-methylcycloheptylmethyl, 1-ethylcycloheptylmethyl, 2-ethylcycloheptylmethyl, 3-ethylcycloheptylmethyl, 4-ethylcycloheptylmethyl, 2-(l-methylcycloheptyl)ethyl, 2 -(2-methylcycloheptyl)ethyl, 2-(3-methylcycloheptyl)ethyl, 2-(4-methylcycloheptyl)ethyl, 2-(1-ethylcycloheptyl)ethyl, 2-(2-ethylcycloheptyl)ethyl, 2-(3-ethylcycloheptyl) )ethyl, 2-(4-ethylcycloheptyl)ethyl, 1-methylcyclooctylmethyl, 2-methylcyclooctylmethyl, 3-methylcyclooctylmethyl, 4-methylcyclooctylmethyl, 5-methylcyclooctylmethyl, l-ethylcyclooctyl tylmethyl, 2-ethylcyclooctylmethyl, 3-ethylcyclooctylmethyl, 4-ethylcyclooctylmethyl, 5-ethylcyclooctylmethyl, 2-(l-methylcyclooctyl)ethyl, 2-(2-methylcyclooctyl)ethyl, 2-(3-methylcyclooctyl)ethyl, 2-(4- methylcyclooctyl)ethyl, 2-(5-methylcyclooctyl)ethyl, 2-(1-ethylcyclooctyl)ethyl, 2-(2-ethylcyclooctyl)ethyl, 2-(3-ethylcyclooctyl)ethyl, 2-(4-ethylcyclooctyl)ethyl and 2 -(5-ethylcyclooctyl)ethyl, 1-fluoro-l-cyclohexylmethyl, 2-fluorocyclohexylmethyl, 3-fluorocyclohexylmethyl, 4-fluorocyclohexylmethyl, 1,1-difluoro-1-cyclohexylmethyl, 2,2-difluoro-l-cyclohexylmethyl, 3,3 -difluoro-l-cyclohexylmethyl, 4,4-difluoro-1-cyclohexylmethyl, 1-fluoro-l-cycloheptylmethyl, 2-fluorocycloheptylmethyl, 3-fluorocycloheptylmethyl, 4-fluorocycloheptylmethyl, l,l-difluoro-1-cycloheptylmethyl, 2,2 -difluorocycloheptylmethyl, 3,3- difluorocycloheptylmethyl, 4,4-difluorocycloheptylmethyl, 1-fluoro-1-(3-methylcyclohexyl)methyl, 2-fluoro-3-methylcyclohexylmethyl, 3-fluoro-3-methylcyclohexylmethyl, 4-fluoro-3- methylcyclohexylmethyl, 1,1-difluoro-3-methylcyclo hexylmethyl, 2,2-difluoro-3-methylcyclohexylmethyl, 3-fluoro methylcyclo hexylmethyl, 4,4-difluoro-3-methylcyclohexylmethyl, 1-fluoro-2-cyclopentylethyl, 2-(2-fluorocyclopentyl)ethyl, 2-(3- fluorocyclopentyl)ethyl, 1,1-difluoro-2-cyclopentylethyl, 2-(2,2-difluorocyclopentyl)ethyl, 2-(3,3-difluorocyclopentyl)ethyl 1,1-difluoro-2-(3,3-difluorocyclopentyl) )ethyl;

cycloalkylidenealkyl groups such as cyclopropylideneethyl, cyclopropyldenpropyl, cyclopropylidenebutyl, cyclopropyl denpentyl, cyclobutylideneethyl, cyclobutylidenepropyl, cyclobutylidenebutyl, cyclobutylidenepentyl, cyclopentylideneethyl, cyclopentylidenepropyl, cyclopentylidenebutyl, cyclopentylidenepentyl, cyclohexylidenebutyl, cyclohexylidenepropyl, cyclohexylidenebutyl, cyclohexylidenepentyl, cycloheptyldenyl , cyclooctylideneethyl, cyclooctylidenepropyl, cyclooctylidenebutyl and cyclooctylidenepentyl, and those cycloalkylidene alkyl groups in which optionally any one of 1 to 6 hydrogen atoms is substituted by a fluorine atom(s);

cycloalkylalkenyl groups such as cyclopropylpropenyl, cyclopropylbutenyl, cyclopropylpentenyl, cyclopropylhexenyl, cyclopropylheptenyl, cyclobutylpropenyl, cyclobutylbutenyl, cyclobutylpentenyl, cyclopentylpropenyl, cyclopentylbutenyl, cyclopentylpentenyl, cyclohexylpropenyl, cyclohexylbutenyl, cyclohexylpentenyl, cycloheptylpropenyl and cyclooctylpropenyl, and those cycloalkylalkenyl groups in which any of 6 hydrogen atoms are substituted with fluorine atom(s);

cycloalkylalkynyl groups such as cyclopropylpropynyl, cyclopropylbutynyl, cyclopropylpentynyl, cyclopropylhexynyl, cyclopropylheptynyl, cyclobutylpropynyl, cyclobutylbutynyl, cyclobutylpentynyl, cyclopentylpropynyl, cyclopentylbutynyl, cyclopentylpeutinyl, cyclohexylpropynyl, cyclohexylbutynyl and cyclohexylpentynyl, and those cycloalkenylalkyl groups in which optionally any of 1 to 6 hydrogen atoms are substituted with fluorine atom(s);

cycloalkenylalkyl groups in which any optional hydrogen atom(s) on the cycloalkenyl ring may be replaced with a lower alkyl group(s), such as cyclopropenylethyl, cyclopropenylpropyl, cyclopropenylbutyl, cyclopropenylpentyl, cyclopropenylhexyl, cyclopropenylheptyl, cyclobutenylethyl, cyclobutenylethyl, cyclobutenylpropyl , cyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl, cycloheptenylmethyl, cycloheptenylethyl, cyclooctenylmethyl, cyclooctenylethyl, (l-methyl-2-cyclopentenyl)methyl, (l-methyl-3-cyclopentenyl)methyl, (2-methyl-l-cyclopentenyl)methyl, (2 -methyl-2-cyclopentenyl)methyl, (2-methyl-3-cyclopentenyl)methyl, (5-methyl-2-cyclopentenyl)methyl, (5-methyl-1-cyclopentenyl)methyl, (3-methyl-1-cyclopentenyl )methyl, (3-methyl-2-cyclopentenyl)methyl, (3-methyl-3-cyclopentenyl)methyl, (4-methyl-2-cyclopentenyl)methyl, (4-methyl-1-cyclopentenyl)methyl, (l- methyl-2-cyclohexenyl)methyl, (1-methyl-3-cyclohexenyl)methyl, (2-methyl-1-cyclohexenyl)methyl, (2-methyl-2-cyclohexenyl)methyl, (2-meth yl-3-cyclohexenyl)methyl, (6-methyl-3-cyclohexenyl)methyl, (6-methyl-2-cyclohexenyl)methyl, (6-methyl-1-cyclohexenyl)methyl, (3-methyl-1-cyclohexenyl) methyl, (3-methyl-2-cyclohexenyl)methyl, (3-methyl-3-cyclohexenyl)methyl, (5-methyl-3-cyclohexenyl)methyl, (5-methyl-2-cyclohexenyl)methyl, (5-methyl -1-cyclohexenyl)methyl, (4-methyl-1-cyclohexenyl)methyl, (4-methyl-2-cyclohexenyl)methyl, (4-methyl-3-cyclohexenyl)methyl, (1-methyl-2-cycloheptenyl)methyl , (1-methyl-3-cycloheptenyl)methyl, (1-methyl-4-cycloheptenyl)methyl, (2-methyl-1-cycloheptenyl)methyl, (2-methyl-2-cycloheptenyl)methyl, (2-methyl- 3-cycloheptenyl)methyl, (2-methyl-4-cycloheptenyl)methyl, (7-methyl-3-cycloheptenyl)methyl, (7-methyl-2-cycloheptenyl)methyl, (7-methyl-1-cycloheptenyl)methyl, (3-methyl-1-cycloheptenyl)methyl, (3-methyl-2-cycloheptenyl)methyl, (3-methyl-3-cycloheptenyl)methyl, (3-methyl-4-cycloheptenyl)methyl, (6-methyl-3 -cycloheptenyl)methyl, (6-methyl-2-cycloheptenyl)methyl, (6-methyl-1-cycloheptenyl)methyl, (4-methyl-1-cycloheptenyl)methyl, (4-methyl-2-cyclo loheptenyl)methyl, (4-methyl-3-cycloheptenyl)methyl, (4-methyl-4-cycloheptenyl)methyl, (5-methyl-3-cycloheptenyl)methyl, (5-methyl-2-cycloheptenyl)methyl, (5 -methyl-1-cycloheptenyl)methyl, (1-methyl-2-cyclooctenyl)methyl, (1-methyl-3-cyclooctenyl)methyl, (1-methyl-4-cyclooctenyl)methyl, (2-methyl-1-cyclooctenyl )methyl, (2-methyl-2-cyclooctenyl)methyl, (2-methyl-3-cyclooctenyl)methyl, (2-methyl-4-cyclooctenyl)methyl, (8-methyl-4-cyclooctenyl)methyl, (8- methyl-3-cycloctenyl)methyl, (8-methyl-2-cyclooctenyl)methyl, (8-methu-1-cyclooctenyl)methyl, (3-methyl-1-cyclooctenyl)methyl, (3-methyl-2-cyclooctenyl) methyl, (3-methyl-3-cyclooctenyl)methyl, (3-methyl-4-cyclooctenyl)methyl, (7-methyl-4-cyclooctenyl)methyl, (7-methyl-3-cyclooctenyl)methyl, (7-methn -2-cyclooctenyl)methyl, (7-methyl-1-cyclooctenyl)methyl, (4-methyl-1-cyclooctenyl)methyl, (4-methyl-2-cyclooctenyl)methyl, (4-methyl-3-cyclooctenyl)methyl , (4-methyl-4-cyclooctenyl)methyl, (6-methyl-4-cyclooctenyl)methyl, (6-methyl-2-cyclooctenyl)methyl, (6-methyl-1-cyclooctenyl)methyl, (5-methyl- l-cyclooctene yl)methyl, (5-methyl-2-cyclooctenyl)methyl), (5-methyl-3-cyclooctenyl)methyl and (5-methyl-4-cyclooctenyl)methyl, and those cycloalkenylalkyl groups in which optionally any of 1 to 6 hydrogen atoms substituted with fluorine atom(s); AND

cycloalkenylalkenyl groups in which any of the hydrogen atoms on the cycloalkenyl ring may be substituted with lower alkyl such as cyclopropenylpropenyl, cyclopropenylbutenyl, cyclobutenylbutenyl, cyclopentenylpropenyl, cyclopentenylbutenyl, cyclopropenylpentenyl, cyclopropenylhexenyl, cyclopropenylheptenyl, cyclobutenylpropenyl, cyclohexenylpropenyl, and cyclohexenylalkenyl groups, and those in optionally any of 1 to 6 hydrogen atoms substituted with fluorine atom(s).

"Aralkyl (any 1 to 3 ring hydrogen atoms in an aralkyl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonylorn, halogen, lower alkoxy, amino, or lower alkylamino)" means unsubstituted or substituted C7- C12 aralkyl groups. Examples thereof include unsubstituted benzyl, phenethyl, phenylpropyl, and naphthynetyl, and those substituted with the substituents listed above.

"Arylalkenyl (any 1 to 3 hydrogen atoms on the ring in the arylalkenyl group can be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonylorn, halogen, lower alkoxy, amino and lower alkylamino)" means unsubstituted or substituted C8- C12 arylalkenyl groups, examples of which include unsubstituted phenylpropenyl and naphthylpropenyl, and those substituted with the substituents listed above.

Examples of "heteroarylalkyl having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (any 1 to 3 ring hydrogen atoms in the heteroarylalkyl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino)" includes unsubstituted 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thiazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolylmethyl, 3- pyrazolylmethyl, 4-pyrazolylmethyl, 2-pyrrolylmethyl, 3-furylmethyl, 2-pyrroylmethyl, 3-pyrroylmethyl, 2-pyrimidiniylmethyl, 4-pyrimidinylmethyl, S-pyrmiidinylmethyl, pyrazinylmethyl, 3-pyridazinylmethyl, 4-quinolylmethyl, 4- quinolylmethyl, 5-quinolylmethyl, 6-quinolylmethyl, 7-quinolylmethyl, 8-quinolylmethyl, 1-isoquinolylmethyl, 3-isoquinolylmethyl, 4-isoquinolylmethyl, 5-isoquinolylmethyl, 6-isoquinolylmethyl, 7-isoquinolylmethyl, 8-isoquinolylmethyl, 2-benzothienylmethyl, 3-benzothienylmethyl, 4-b enzothienylmethyl, 5-benzothienimiethyl, 6-benzothienylmethyl, 7~benzothienmethyl, 2-imidolylmethyl, 3-indolylmethyl, 4-indolylmethyl, 5-indolylmethyl, 6-indolylmethyl, 7-indolylmethyl, 2-benzimidazolylmethyl, 4-benzimidazolylmethyl, 2-benzothiazolylmethyl, 4-benzothiazolylmethyl, 5-benzothiazolylmethyl, 6-benzothiazolylmethyl, 7-benzothiazolylmethyl, 2-benzoxazolylmethyl, 4-benzoxazolylmethyl, 5-benzoxazolylmethyl, 6-benzoxazolylmethyl, 7-benzoxazolylmethyl, 2-benzofuranylmethyl, 4-benzofuranylmethyl, 4-benzoxazolylmethyl benzofuranylmethyl, 5-benzofuranylmethyl, 6-benzofuranylmethyl, 7-benzofuranylmethyl, 2-pyridylethyl, 2-pyridylpropyl, 3-pyridylethyl, 4-pyridylethyl, 2-thiazolylethyl, 2-thienylethyl, 3-thienylethyl, 1-imidazolylethyl, 2-imidazolylethyl, 3-pyrazolylethyl, 4-pyrazolylethyl, 2-furylethyl, 3-furylethyl, 2-pyrrolylethyl, 3-pyrrolylethyl, 2-pyrimidinylethyl, 4-pyrimidinylethyl, 5-pyrimidinylethyl, pyrazinylethyl, 3-pyridazinylethyl, 4-pyrazolylethyl, 2-quinylethyl, 2-benzothienylethyl, 3-benzothienylethyl, 4-benzothienylethyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 2-indolylethyl, 4-indolylethyl, 5-indolylethyl, 6-indolylethyl, 7-indolylethyl, 2-benzimidazolylethyl, 4-benzimidazolylethyl, 5-benziirddazolylethyl, 2-benzothiazolylethyl, 4- benzothiazolylethyl, 5-benzothiazolylethyl, 6-benzothiazolylethyl, 7-benzothiazolylethyl, 2-benzoxazolylethyl, 4-benzoxazolylethyl, 5-benzoxazolylethyl, 6-benzoxazolylethyl, 7-benzoxazolylethyl, 2-benzofuranylethyl, 3-benzofuranylethyl, 5-benzoxazolylethyl, 6-benzofuranylethyl and 7-benzofuranylethyl, and those substituted with the substituents listed above.

As examples "heteroarylalkenyl having 1-2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (any 1 to 3 ring hydrogen atoms in the heteroarylalkyl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro , lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino)" are unsubstituted 2-pyridylpropenyl, 3-pyridylpropenyl, 4-pyridylpropenyl, 2-thiazolylpropenyl, 2-thienylpropenyl, 3-thienylpropenyl, 1-imidazolylbutenyl, 2-imidazolylpropenyl, 1, 3 -pyrazolylpropenyl, 4-pyrazolylpropenyl, 2-rurylpropenyl, 3-rurylpropenyl, 2-pyrrolylpropenyl, 3-pyrrolylpropenyl, 2-pyrimidinylpropenyl, 4-pyrimidinylpropenyl, 5-pyrimidinylpropenyl, pyrazinylpropenyl, 3-pyridazinylpropenyl, 2-pyramidinylpropenyl, 2-pyramidinylpropenyl. -benzothienylpropenyl and 2-indolylpropenyl, and those substituted with the above named substituents may be mentioned.

"Halogen" includes fluorine, chlorine, bromine and iodine.

"Lower alkyl" means C1-C6 straight chain or branched alkyl groups, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, bexyl and isohexyl groups.

"Lower Alkoxy" refers to C1-C6 straight chain or branched alkoxy groups, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, hexyloxy and isohexyloxy groups.

"Lower alkoxycarbonyl" refers to C1-C6 straight chain or branched alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups.

"Aralkyloxycarbonyl" refers to C7-C10 aralkyloxycarbonyl groups, for example, benzyloxycarbonyl and phenethyloxycarbonyl groups.

"Lower alkylamino" means C1-C6 straight chain or branched alkylamino groups, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, t-butylamino, pentylamino, isopentylamino, hexylamino, isohexylamino, dimethylamino, diethylamino and dipropylamino groups .

"Protected hydroxyl groups" means hydroxyl groups that are protected with an acyl such as acetyl, an alkylsilyl such as trimethylsilyl and t-butyldimethylsilyl, an aralkyl such as benzyl and trityl, an ether group such as methoxymethyl, and in the form of an alkylideneketal such as isopropylideneketal .

"Oxo protecting groups" means oxo groups that are protected in acetal or ketal form such as ethylene ketal, trimethylene ketal and dimethyl ketal.

"Protected amino or lower alkylamino groups" means amino or lower alkylamino groups which are protected, for example, with aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl and trityl; lower alkanoyl groups such as formyl, acetyl and propionyl; arylalkanoyl groups such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl and t-butoxycarbonyl; alkenyloxycarbonyl groups such as 2-propenyloxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl, and lower alkylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl. Particularly preferred are amino or lower alkylamino groups protected with t-butoxycarbonyl and benzyloxycarbonyl groups.

Also, "deprotection" means the removal of a protecting group by means of conventional procedures used in organic chemistry, such as hydrolysis, hydrogenolysis, and the like.

Referring to the general formula [I],

(1) Ar represents an aryl group or a heteroaryl group having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (any 1 to 3 hydrogen atoms on the ring in said aryl or heteroaryl group can be substituted with a lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino and lower alkylamino). Particularly preferred are unsubstituted phenyl and substituted phenyl having the above-mentioned substituents.

(2) R 1 is C 3 -C 6 cycloalkyl which may have 1 to 4 fluorine atoms on the ring; cyclobutyl, cyclopentyl, cyclohexyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl, 2,2-difluorocyclopentyl, 3,3-difluorocyclopentyl, 2,2,3,3- tetrafluorocyclopentyl, 3,3,4,4-tetrafluorocyclopentyl, 2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl and 4,4-difluorocyclohexyl.

Of these, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclopropyl, 2,2-difluorocyclopentyl, 3,3-difluorocyclopentyl, 2,2,3,3-tetrafluorocyclopentyl, 3-fluorocyclopentyl are particularly preferred. . Most preferred is 3,3-difluorocyclopentyl.

(3) X represents O and NH, NH is preferred.

(4) R2 represents a C5-C15 saturated or unsaturated aliphatic hydrocarbon group whose any of 1 to 6 hydrogen atoms may be substituted with a fluorine atom(s), an aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl group having 1 to 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulfur (optionally any of the 1 to 3 hydrogen atoms on the ring of said aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl group can be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino). Of these, preferred are the groups expressed by the following formula [ii], in which any of 1 to 6 hydrogen atoms may be substituted with fluorine atom(s),

[image]

[where

Q represents methylene, ethylene, trimethylene or tetramethylene;

Ra and Rc each represent a hydrogen atom or together form a single bond; i

Rb, Rd and Re may be the same or different and each represents a hydrogen atom, a lower alkyl group, C3-C8 cycloalkyl or cycloalkenyl, or Rb and Rd, or Rd and Re together form each C3-C8 cycloalkyl or cycloalkenyl],

preferred are benzyl, phenethyl, phenylpropyl, phenylpropenyl, 2-pyridylmethyl, 2-pyridylethyl, 2-pyridylpropyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thiazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl (any of 1 to 3 hydrogens or ring atoms of said benzyl, phenethyl, phenylpropyl, phenylpropenyl or heteroarylalkyl group may be substituted with lower alkyl, trifluoromethyl , cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino).

Particularly preferred are 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyridylmethyl or benzyl (any of the 1-3 ring hydrogen atoms in the thienylmethyl, furylmethyl, pyridylmethyl or benzyl group may be substituted with lower alkyl , trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, amino, lower alkylamino or lower alkoxy), inter alia, a 6-aminopyridin-2-ylmethyl group is preferred.

According to the mode of substitution, the compounds of the present invention may exist as stereoisomers such as optical isomers, diastereoisomers and geometric isomers. It should be understood that the compounds of the present invention also include all such stereoisomers and mixtures thereof.

Moreover, the compounds of the present invention may exist as pharmaceutically acceptable salts. Such salts include salts of inorganic acids such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; salts of organic carboxylic acids such as maleates, fumarates, succinates, tartrates, citrates and ascorbates; salts of organic sulfonic acids such as methanesulfonates, isethionates, benzenesulfonates and p-toluenesulfonates; and the like.

Compounds of the above general formula [I] according to the present invention can be prepared, for example, with:

(a) by the reaction of a carboxylic acid of the general formula [III]

[image]

[wherein Ar represents an aryl group or a heteroaryl group having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (any 1 to 3 ring hydrogen atoms in said aryl or heteroaryl group may be substituted with lower alkyl , trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino); R10 represents C3-C6 cycloalkyl in which any of 1 to 4 hydrogen atoms may be substituted by a fluorine atom(s) or C3-C6cycloalkyl having 1 to 2 protected or unprotected hydroxyl or oxo groups] or a reactive derivative thereof with a compound of the general formula [IV]

[image]

[where R20 represents a C5-C15 saturated or unsaturated aliphatic hydrocarbon group in which any of 1 to 6 hydrogen atoms may be substituted with fluorine atom(s), a C5-C15 saturated or unsaturated aliphatic hydrocarbon group having 1-2 protected or unprotected hydroxyl or oxo groups, aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl group having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (optionally any of 1 to 3 hydrogen atoms on the ring in said aralkyl, an arylalkenyl, heteroarylalkyl or heteroarylalkenyl group may be substituted with a lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, unprotected or protected amino, unprotected or protected lower alkylamino or aralkyloxycarbonyl group) and X is NH ih O] ; and when either R10 or R20 has an unprotected or protected 1 to 2 hydroxyl or oxo group(s) converting said hydroxyl or oxo group(s) to a fluorine atom(s) either as such or after removal of the protecting group(s); when R10 and R20 have protected amino or protected lower alkylamino group(s); and when R 10 or R 20 has lower alkoxycarbonyl or aralkyloxycarbonyl, converting the same to amino; or

(b) by the reaction of a carboxylic acid of the above general formula [III] or its reactive derivative with a compound of the general formula [V]

[image]

[where E is a protecting group for an imino group and X is as defined above] or a salt thereof; by deprotection of the resulting compound of the general formula [VI]

[image]

[wherein Ar, R10, X and E are as defined above] thereafter by reacting the same with a compound of general formula [VII]

R20-L [VII]

[where L represents a leaving group and R20 is determined as above] in the presence of alkali, if necessary, and again if necessary by conducting the conversion reaction of R10 and R20 similarly as above; or

(c) deprotection of the compound of general formula [VI] above and subjecting it to reductive alkylation with a compound of general formula [VIII]

R21-CHO [VIII]

[where R21 represents a C4-C14 saturated or unsaturated aliphatic hydrocarbon group in which any of l to 6 hydrogen atoms may be substituted with fluorine atom(s), a C4-C14 saturated or unsaturated aliphatic hydrocarbon group having unprotected or protected l to 2 hydroxyl or oxo groups, aryl, aralkyl, arylalkenyl or heteroaryl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (optionally any 1-3 ring hydrogen atoms in said aryl , aralkyl, arylalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl groups can be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, unprotected or protected lower alkylamino and aralkyloxycarbonyl)], and if necessary by carrying out the reaction R10 and R21 according to the previous one.

In the above formula [VII], the "leaving groups" represented by L include, for example, halogen atoms such as chlorine, bromine or iodine; alkylsulfonyloxy groups such as methanesulfonyloxy; and arylsulfonyloxy groups such as p-toluenesulfonyloxy.

In the above formulas [V] and [VI], "protecting groups for the imino group" represented by E means protecting groups as above for amino.

In the process variant (a) described above, a carboxylic acid of formula [III] is reacted with a compound of formula [IV] or a salt thereof in the presence of a suitable condensing agent. Therefore, the bound compound of the general formula [IX] was obtained

[image]

[where Ar, R10, X and R20 are as defined above].

The carboxylic acid of formula [III], used as a starting material in the above condensation reaction, can be prepared, for example, by the process as described in Reference Examples.

The condensing agent to be used in the above reaction may be any of those commonly used in the field of organic synthetic chemistry for condensation reactions of carboxyl groups with hydroxyl or amino groups, and examples thereof include N,N'-dicyclohexylcarbodiimide, l-ethyl -3-(3-dimethyl-aminopropyl)carbodiimide, diphenylphosphoryl azide and dipyridyl disimide-triferrulphosphine. Of these, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is preferred.

The use of these condensing agents is not subject to a critical limitation, while it is usually in the range of 1 to 5 equivalents, preferably 1 to 2 equivalents per mole of the compound of formula [III].

If necessary, the condensation reaction described above can be carried out in the presence of alkali. Bases which can be used for this purpose include, for example, aliphatic tertiary amines such as triethylamine and diisopropylethylamine; and aromatic amines such as pyridine, 4-dimethylaminopyridine, quinoline. Particularly preferred is 4-dimethylaminopyridine.

The condensation reaction is preferably carried out in an inert solvent. Suitable inert solvents include, for example, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, and mixtures of the foregoing solvents. Of these, diethyl ether, tetrahydrofuran, N,N-dimethylformamide and dioxane are preferred.

The reaction temperature may typically range from -70°C to the boiling point of the reaction solvent used and preferably from -20°C to 100°C. Under these conditions, the reaction can usually be completed within a time range of from 5 minutes to 7 days and preferably from 10 minutes to 24 hours.

The ratios of the compound of the formula [IV] or its salt to the compound of the formula [III] are not dangerous and may vary according to the type of individual compounds, the applied reaction conditions and other factors. Thus, the compound of the formula [IV] or its salt can be usually used in an amount of 1 to 5 moles, preferably 1 to 2 moles, per mole of the compound of the formula [III].

The bound compound of the above formula [IX] can also be obtained by converting the carboxylic acid of the formula [III] into its reactive derivative and condensing it with the compound of the formula [IV] or its salt.

Suitable reactive carboxylic acid derivatives of formula [III] include, for example, compounds commonly used in the field of organic synthetic chemistry to activate the carboxyl group(s) in an esterification or amidation reaction, such as mixed acid anhydrides, active esters and active amides .

Mixed acid anhydrides of a carboxylic acid of formula [III] can be obtained by reacting a carboxylic acid of formula [III] with an alkyl chlorocarbonate, for example ethyl chlorocarbonate, an aliphatic carboxylic acid chloride, for example acetyl chloride, pivaloyl chloride or the like according to conventional methods. Their reactive esters can be obtained by reacting a carboxylic acid of formula [III] with an N-hydroxy compound, for example N-hydroxysuccinimide, N-hydroxyphthamide or 1-hydroxybenztriazole; or a phenolic compound, for example 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol or the like; in the presence of a condensing agent, for example N,N'-dicMohexylcarbodiimide, 1-ethyl-3-(3-dunethylaminopropyl)carbodiimide, diphenylphosphoryl azide or dipyridyl disulfithiphenylphosphine, according to conventional procedures. Their reactive amides can be obtained by reacting the carboxylic acid of formula [III] with 1,1-dicarbonyl-diimidazole, 1,1-carbonylbis(2-methylimidazole) or according to usual procedures.

The condensation reaction of the reactive carboxylic acid derivative [III] with the compound of the formula [IV] or its salt is preferably carried out in an inert solvent. Suitable inert solvents include, for example, diethyl ether, tetrahydrofuran, N,N-dimethylformamide 3 dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, and mixtures of the foregoing solvents. Of these, diethyl ether, chloroform, tetrahydrofuran, N,N-dimethylformamide and dioxane are preferred.

The reaction temperature may typically range from -70°C to the boiling point of the reaction solvent used and preferably from -20°C to 100°C.

The ratios of the compound of formula [IV] or its salt to the reactive carboxylic acid derivative of formula [III] are not dangerous and may vary according to the type of individual compounds, the conditions of the applied reaction and other factors. Thus, the compound of the formula [IV] or its salt can usually be used in an amount of 1 to 5 mol, preferably 1 to 2 mol, per mol of the reactive carboxylic acid derivative of the formula [III].

In the bonded compounds expressed by the general formula [IX], when R10 is a C3-C6 cycloalkyl group having 1-2 unprotected or protected hydroxyl or oxo groups, or R20 is an aliphatic hydrocarbon group having 1-2 unprotected or unprotected hydroxyl or oxo groups (e), are converted to fluorine atom(s) either as is or after removal of the protecting group(s).

Deprotection of ketal-protected hydroxyl and oxo groups in compounds of formula [IX] can be conventionally carried out in an aqueous solvent, using an inorganic acid, an organic acid, a weak hydrogen peroxide, or the like. Suitable inorganic acids include, for example, hydrochloric acid and sulfuric acid; suitable organic acids include, for example, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and acetic acid; and suitable weak oxygen salts include, for example, ammonium chloride and pyridinium p-toluenesulfonate. Preferred aqueous solvents include aqueous ethanol, aqueous ethanol, aqueous tetrahydrofuran, aqueous dioxane, and the like. The reaction can usually be carried out in the presence of a catahtic amount of up to 5 equivalents, preferably a catahtic amount of up to 1 equivalent, of such acids at a temperature ranging from 0°C to 100°C and preferably from room temperature to 80°C.

Conversion of the hydroxyl or oxo group(s) to fluorine atom(s) can usually be achieved by reacting the compound in an inert solvent that does not harm the reaction, for example methylene chloride, chloroform, tetrahydrofuran, rethanol, acetonitrile, dimethylsulfoxide or pyridine, or in the absence of a solvent, using one equivalent to an excess, preferably 1-2 equivalents, of a fluorinating agent such as sulfur tetrafluoride, diethylaminosulphur trifluoride, cesium fluorosulfate, tetrabutylammonium fluoride, tris(dimethylamino)sulfonium-difluoromethylsilicate, hydrogen fluoride or tosyl fluoride, preferably at a temperature in the range of -80° C - 180°C for 10 minutes to 72 hours.

When R20 in the compounds expressed by the general formula [IV] or [IX] has a protected amino group(s) or a protected lower alkylamino group(s), the protecting group(s) are removed if necessary; when lower alkoxycarbonyl or aryloxycarbonyl group(s) are present, the functional group(s) are conveniently converted to amino group(s). Removal of amino protecting groups is achieved by a process known per se. for example, any of those described in Protective Groups in Organic Synthesis. T.W. Greene, John Wiley & Sons Co. (1981) or by methods analogous thereto, for example, solvolysis using acid or alkali, chemical reduction using metal hydride complexes or the like and catalytic reduction using palladium on charcoal, Raney-nickel or the like.

Acid solvolysis can usually be carried out by treating the compound with an acid such as formic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid, in an inert solvent such as methylene chloride, anisole, tetrahydrofuran, dioxane, methanol or ethanol or mixtures of such solvents and of water, or in the absence of a solvent, preferably at temperatures ranging from about 0°C to about 100°C, for a period of time ranging from 10 minutes to 24 hours.

Solvolysis with alkali can be carried out conventionally by treating the compound with an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal carbonate, for example sodium carbonate or potassium carbonate, in an inert solvent which does not adversely affect the reaction, for example, methanol, ethanol, isopropanol, tetrahydrofuran or dioxane or a mixture of such solvents with water, preferably at temperatures in the range of about -20 °C to about 80°C, over a period of time ranging from 10 minutes to 24 hours.

The catalytic reduction can usually be carried out in the presence of a catalyst such as palladium on charcoal, palladium hydroxide, Raney nickel or platinum oxide, in an inert solvent, for example methanol, ethanol, water or acetic acid or a mixture of such solvents, preferably under a hydrogen pressure of about 1 to about 20 kg/cm2, preferably at temperatures ranging from about 0°C to about 40°C, over a period of time ranging from 10 minutes to 24 hours.

The conversion of a lower alkoxycarbonyl or aryloxycarbonyl into an amino can be carried out either by reacting the compound with hydrazine to form an acid hydrazide and then by converting it into the corresponding acid azide; or by converting the compound to a carboxylic acid by hydrolysis, then to an acid azide, followed by a partitioned hydrolysis.

In a variant of process (b), the condensation reaction of a carboxylic acid of formula [III] and its reactive derivative with a piperidine derivative of formula [V] in the first step can be used in a manner similar to the condensation reaction of a carboxylic acid of formula [III] or its reactive derivative with a compound of formula [IV] in the version of procedure (a).

The compound of the preceding formula [VI] obtained through this condensation reaction is then deprotected from the imino group(s).

Removal of said imino protecting group(s) from the compound of formula [VI] can be achieved in a manner similar to the removal of amino protecting groups described above.

The thus obtained compound of the general formula [X]

[image]

[where Ar, R 10 and X are as defined above] is reacted with a compound of formula [VII] in a second step, if necessary in the presence of a base.

The reaction of a compound of formula [X] with a compound of formula [VII] is usually carried out in a suitable solvent using exactly equimolar amounts of the compounds or using either compound in slight excess (for example using a compound of formula [VII] in an amount of 1 to 1.3 mol per mole of compound of formula [X]). If desired, however, any of the compounds may be used in large excess. What's more, a suitable alkali and/or some additive can be used.

Suitable solvents include, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; aprotic polar solvents such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide; and their mixtures.

Bases that can be used for the reaction described above include, for example, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrohidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene ( DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, and isoquinoline. Of these, N,N-diisopropylethylamine and potassium carbonate are preferred.

Additives that can be used for the reaction described above include, for example, alkali metal iodides such as lithium iodide, sodium iodide and potassium iodide. Of these, potassium iodide is preferred.

The reaction temperature may typically range from about 0°C to the boiling point of the solvent, and the reaction time may typically range from 10 minutes to 48 hours. If desired, however, reaction conditions outside these limitations may be used.

If necessary, furthermore, the conversion reaction of R10 and R20 is carried out as described according to the version of procedure (a).

The reductive alkylation reaction of the compound of the above formula [X] with the aldehyde of the formula [VIII] according to the version of procedure (c) is usually carried out in an inert solvent that does not adversely affect the reaction. Suitable inert solvents include, for example, alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; and their mixtures. Of these, methanol, ethanol, tetrahydrofuran and toluene are preferred. The reaction temperature may typically range from about -30°C to about 200°C and preferably from about 0°C to about 100°C. The reaction time may typically range from 10 minutes to 7 days and preferably from 10 minutes to 24 hours.

The reductive alkylation reaction described above is preferably carried out under weakly acidic conditions that facilitate the formation of Schiff base. Acids that can be used for necessary pH control include, for example, p-toluenesulfonic acid, hydrochloric acid, and trifluoroacetic acid.

Reductive alkylation can be achieved, for example, using a metal hydride complex such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or sodium triacetoxyborohydride, or by catalytic reduction using a palladium-on-charcoal catalyst, a Raney nickel catalyst or the like. It is preferably achieved using a metal hydride complex such as sodium borohydride or sodium cyanoborohydride. In particular, when the reductive alkylation is carried out under weakly acidic conditions that facilitate the formation of Schiff's alkali, it is preferable to use sodium cyanoborohydride or the like, which are relatively stable in the acidic pH range.

When a metal hydride complex is used as the reducing agent, the amount of reducing agent used may typically range from 1 mole to an excess of moles, preferably from 1 to 10 moles, per mole of the compound of formula [X].

If necessary, then the conversion reactions of R10 and R21 are carried out as described for the variant of procedure (a).

The compounds of formula [I] obtained according to the above-described versions of process (a), (b) and (c) can be isolated and purified by those methods known per se, i.e. by such commonly used separations as column chromatography using silica gel, adsorbing resin or the like, liquid chromatography, thin layer chromatography, solvent extraction or recrystallization and reprecipitation.

The compounds of the present invention and their intermediates exist in stereoisomeric forms such as enantiomeric isomers, diastereoisomers and geometric isomers. It is to be understood that the compounds of the present invention also include all such stereoisomeric pure substances and mixtures thereof. When the compounds of the present invention and their intermediates are racemates, their optical separation can be achieved by conventional means such as high performance liquid chromatography using a chiral support or fractional crystallization of a diastereomeric salt.

The compounds of formula [I] obtained in the manner described above can be converted into their pharmaceutically acceptable salts according to conventional methods. Conversely, such salts can also be converted into the corresponding free amines according to conventional methods.

The compounds of formula [I] in accordance with the present invention show a strong and selective inhibitory action for binding to muscarinic receptors, a strong and selective antagonism towards muscarinic receptors in vitro and, furthermore, a strong and permanent bronchodilator action in vivo. These demonstrated actions of the compounds of the present invention are shown with the following tests for inhibition of binding to muscarinic receptors and tests for antagonism against different muscarinic receptors.

Inhibition studies of binding to muscarinic receptors

These tests were performed according to a modified procedure of Hargreaves et al. (No. J. Pharmacol. 107: 494-501, 1992). Membranes from CHO cells expressing cloned human ml-m5 (Receptor Biology, Inc.) were incubated with 0.2 nM [ 3 H]-N-methylscopolamine with each compound of the present invention tested at 0.5 mT. 50 mM Tris-HCl - 10 mM MgCl2 - 1 mM EDTA (pH 7.4) for 2 hours at 25°C. Free and membrane-bound [3H]-N-methylscopolamine was separated by filtration through a glass filter (UniFilter-GF/C; Packard Instruments Co., Inc.) using a collector (Filtermate™ 196; Packard Instruments Co., Inc.). Then the filter was washed four times with 1 mL of ice-cold Tris-HCl (pH 7.4) and dried at 50°C. After addition of scintillator (Microscinti 0; Packard Instruments Co., Inc.), radioactivity was measured with a liquid scintillation counter (TopCount™; Packard Instruments Co., Inc.).

Nonspecific binding was measured in the presence of 1 μM N-methylscopolamine. According to the method of Cheng and Prussoff (Biochem. Pharmacol. 22: 3099-3108, 1973), the binding affinity (Ki value) of a test compound (that is, a compound of the present invention) to muscarinic receptors was calculated from the concentration of the test compound that achieved 50% inhibition binding of [3H]-N-methylscopolamine (IC50 value).

Table 1

Inhibitory effects on binding to muscarinic M2 and M3 receptors

[image]

As is clear from the results listed in Table 1 above, these compounds of the present invention have shown far greater inhibitory activity on binding to the M3 receptor than to the M2 receptor.

Tests of antagonism towards muscarinic receptors (in vitro)

1) Tests of antagonism according to the M2 recipe in the isolated right atrium of rats

These tests were performed according to the usual procedure. Male SD rats (weight 300-500 g) were killed by exsanguination, and the right atrium was isolated. This preparation was isometrically suspended in an organic bath with 20 mL of Krebs-Henseleit solution (aerated with 95% O2 - 5% CO2 and kept at 32°C) with an initial tension of 0.5 g. The heart was recorded with a heart rate counter. After the preparation was equilibrated for 30 minutes, carbachol (10-9 to 10-6 M) was cumulatively administered in a three-fold increased dose. Therefore, heart rate reduction was measured to obtain a dose-dependent curve for the control experiment. After the preparation was washed with fresh solution to restore cardiac output, the test compound was then administered. Ten minutes later carbachol was again cumulatively given. Responses to carbachol are expressed as a percentage based on cardiac output before carbachol administration as 100%. The antagonistic potential (KB value) of the test compound was determined from the degree of shift from the dose-response curve obtained by treating the individual test compound of the present invention.

2) Tests for antagonism according to the M3 prescription in isolated rat trachea

These tests were performed according to the usual procedure. A male CD rat (weight 300-500 g) was killed by exsanguination, and the trachea was isolated. Annular sections (2 mm wide) were cut from the trachea and cut transversely at the anterior cartilage portion to make an open ring preparation. The preparation was suspended in a Magnus tube filled with 5 mL of Krebs-Henseleit solution (aerated with 95% O2 - 5% CO2 and kept at 32°C) with an initial tension of 1.0 g and a resting tension of 0.6 g. The tension of the preparation is shot isometrically. After equilibration for one hour, the preparation was clamped twice by treatment with 10-4 M carbachol, and the second clamp induced with carbachol was used as a reference clamp. After the preparation was washed with fresh solution to restore the basic union, the test compound was given (or without treatment). Ten minutes later, diurnal carbachol (10-8 to 10-3 M) cumulatively in a three-fold increased dose to obtain a dose-response curve. A dose-response curve was drawn by expressing the response as a percentage based on the reference concentration of the preparation as 100%. The antagonistic potential (KB value) of the test compound was determined from the degree of displacement of the dose-response curve obtained by treatment with the test compound.

Table 2

Antagonism towards muscarinic receptors (in vitro)

[image]

As is clear from the achievements listed in Table 2 above, the compounds of the present invention show far more potent antagonism to the tracheal M3 receptor than to the right ventricular M2 receptor. Therefore, the compounds of the present invention are more selective for the tracheal M3 receptor.

Tests of antagonism towards muscarinic receptors (in vivo)

1-A) Bronchodilation tests in rats (i.v.)

Eight- to eleven-week-old male Sprague-Dawley rats, weighing 380-420 g, were anesthetized with urethane (750 mg/kg, i.p.) and α-chloralose (37.5 mg/kg, i.p.). The bronchus of each rat was intubated, and the right jugular vein was cannulated for drug administration. After spontaneous breathing was suppressed with succinylcholine (5 mg/kg, s.c.), airflow resistance was measured under artificial ventilation using the Pulmonary Mechanics Model 6 (Buxco). In order to induce an increase in airflow resistance, the animals were given acetylcholine (50 μg/kg, i.v.). Acetylcholine-induced increases in airflow resistance were measured 5 minutes before and 5 minutes after administration of the test compound, and the ratio of airflow resistance to each other was calculated. In the control, an isotonic solution of sodium chloride was used instead of the tested compounds and, in addition, the identical procedure was repeated, the calculated ratio was adjusted to 100%. The dose that inhibited the acetylcholine-induced increase in airflow resistance was determined to be the ED50, and the ED50 values of the test compounds were calculated by fair analysis of their dose-response curves.

1-B) Bronchodilation tests in rats (p.o.)

Eight- to eleven-week-old male Srague-Dawley rats, weighing 380-420 g, were orally administered the test compound. Rats were treated in the same way as for i.v. tests, starting 30 minutes after administration, and the values of their resistance to air flow were measured. The increase in airflow resistance induced with acetylcholine (50 μg/kg, i.v.) was measured 60 minutes after administration of the test compounds. In the control, an isotonic solution of sodium chloride was used instead of the tested compounds, and in addition the identical procedure was repeated, the ratio between the two values of resistance to air flow were adjusted to be 100%. The dose that inhibited the increase in resistance induced by acetylchoine in the control group by 50% was determined as the ED50, and the ED50 values of the test compounds were calculated by fair analysis of their dose-response curves.

Table 3

Antagonism according to the muscarinic prescription (in vivo)

[image]

2) Bronchodilation tests in dogs (p.o.)

Twelve- to twenty-four-month-old beagle dogs (weight 10-15 kg) were anesthetized with pentobarbital (30 mg/kg, i.v.) and intubated in their bronchus. Their sensitivity to airflow to inhaled methacholine was measured at least twice at two-week intervals, and dogs showing repeated baseline1) methacholine responses were selected. The tested compounds were administered orally (1 mg/kg) to those dogs with a confirmed initial value of methacholic reaction. Four hours after the administration, a methacholine provocation test was performed, and then the initial value2) of the methacholine reaction after administration of the tested compound was obtained.

The bronchodilatory effect of the tested compound is determined by the following equation:

offset value =

initial value1) metacholic reactions

after drug administration

-------------------------------------------------- -

initial value2) metacholic reactions

without giving medicine

The methaholic provocation test was performed using the Astograph TCK-6100H Model (Chest). Methacholine chloride was used as a bronchoconstrictor, which was diluted with isotonic sodium chloride solution in 10 concentration levels starting from 40,000 μg/mL, then 20,000, 10,000, 5,000, 2,500, 1,250, 625, 312.5, 156 and 78 μg/mL. ml. These methacholine aerosols were inhaled by the test animals, every half minute, starting from the lowest level of concentration, and breathing resistance was continuously recorded. The concentration level at which breathing resistance reached twice the initial value was recorded as the methacholic initial value.

Table 4

Bronchodilatory effect on dogs (oral administration)

[image]

As clearly shown in Table 4 above, the compounds of the present invention exhibit potent bronchodilator activity and a long duration of action.

According to the above, the compounds of formula [I] of the present invention, which are characterized by the introduction of fluorine atom(s), exhibit potent and selective antagonistic) activity against the muscarinic M3 prescription and exhibit excellent oral activity, duration of action and pharmacokinetics. Therefore, they can be given to patients orally or parenterally as safe pharmaceuticals that show few side effects, in the treatment and prevention of such respiratory diseases as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable stomach syndrome, ulcerative colitis, diverticulitis and contraction of the smooth muscles of the digestive system accompanied by pain; urinary disorders such as urinary incontinence and frequency of neurogenic pollakiurea, neurogenic bladder, nocturnal enuresis, bladder incontinence, cystospasm and chronic cystitis; and motion sickness.

In the practical use of the compounds of the present invention for the treatment or prevention of such diseases, they may be combined with pharmaceutically acceptable adjuvants in a conventional manner to prepare pharmaceutical compositions suitable for administration. For this purpose, various adjuvants that are commonly used in the field of pharmaceuticals can be used. Such adjuvants include, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cornstarch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose. , sorbitol, sorbitan ester of fatty acid, posorbates, sucrose ester of fatty acid, polyoxyethylene, hard castor oil, polyvinyl pyrrolidone, magnesium stearate, light anhydrous sialic acid, milovka vegetable oil, benzyl alcohol, acacia, propylene glycol, polyalkylene glycol, cyclodextrin and hydroxypropylcyclodextrin .

Dosage forms of pharmaceutical preparations prepared using these adjuvants include solid preparations such as tablets, capsules, granules, powders and suppositories; liquid preparations such as syrups, elixirs and injections; and the like. These compositions can be prepared according to conventional techniques well known in the field of pharmaceuticals. Liquid preparations may be in a form that is dissolved or suspended in water or other suitable media prior to use. In particular, the injections may be in the form of a solution or suspension in saline or glucose solution, or in the form of a powder for reconstitution by dissolving or suspending in saline or glucose before use.

If desired, such injections may contain buffers and/or preservatives.

As preparations for oral use, such forms of preparations, apart from ordinary tablets, capsules, grains, powders and the like, can be used as aerosols or dry powders for inhalation, elixirs containing spices or dyes or suspensions.

In these pharmaceutical preparations, the compound according to the present invention may be present in a ratio of 1.0 to 100% by weight, preferably 1.0 to 60% by weight, based on the total weight of the preparation. These pharmaceutical preparations may additionally contain other therapeutically effective compounds.

When the compounds of the present invention are used as drugs, their dosage level and dosage schedule may vary according to the sex, age and body weight of the patient, the severity of the symptoms, the type and range of the desired therapeutic effect, and the like. Generally for oral administration, they are preferably given at a daily dose of 0.1 to 100 mg/kg for adults and this daily dose may be given at once or in several divided doses. For parureteral administration, they are preferably given in a daily dose of 0.001 to 10 mg/kg for adults and this daily dose can be given at once or in several divided doses.

Hereinafter, the present invention will be more particularly explained with reference to working examples, it being understood that the examples are in no way limiting the scope of the invention.

Example 1

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of 1-(4-methyl-3-pentenyl)-4-piperidone

To a solution of 2.5 g of 4-piperidone monohydrochloride ionohydrate in 150 mL of acetonitrile, 11 g of potassium carbonate, 2.62 g of 5-bromo-2-methyl-2-pentene, and 800 mg of potassium iodide were sequentially added, and the mixture was heated under reflux through 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 2.24 g of the title compound as a white solid.

Stage 2. Synthesis of 4-amino-1-(4-methyl-3-pentenyl)-piperidine

To solutions of 2.2 g of 1-(4-methyl-3-pentenyl)-4-piperidone in 60 rnL of methanol, 1.1 g of ammonium acetate and 860 mg of sodium cyanoborohydride were added sequentially at room temperature, followed by stirring overnight at same temperature. Methanol was distilled under reduced pressure, the pH of the reaction mixture was adjusted to 3 with 1N hydrochloric acid, after which it was washed with diethyl ether. The aqueous portion was basified with 1N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 1.9 g of the title compound as a colorless oil.

Stage 3. Synthesis of (2R)-N-[1-(4-methyl-3-pentepyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

55 mg of 1,1-carbonyldiimidazole was added to a solution of 75 mg of (2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid in 3 mL of N,N-dimethylformamide at room temperature, after which followed by mixing for 2 hours at the same temperature. Then 60 mg of 4-amino-1-(4-methyl-3-pentenyl)piperidine and 5 mg of 4-dimethylaminopyridine were added sequentially, followed by stirring overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate solution, water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced flame and the residue obtained was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (manufactured by E. Merck); chloroform / methanol = 10/1], to give 23 mg of the title compound as an oil.

1H-NMR (CDCl3, δ ppm): 1.32-1.50 (2H, m), 1.60 (3H, s), 1.68 (3H, s), 1.58-2.34 (12H , m), 2.43-2.49 (IH, m), 2.73-2.82 (3H, m), 3.23-3.36 (IH, m), 3.48 (IH, wide s), 3.62-3.73 (IH, m), 5.03-5.08 (IH, m), 6.29-6.33 (IH, m), 7.25-7.39 ( 3H, m), 7.54-7.57 (2H, m)

FAB-MS low resolution (m/e, (C24H34F2N2O2 + H)+): 421.

Example 2

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared in the same manner as described in step 3 of Example 1 using (2R)-[(1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

1H-NMR (CDCl3, δ ppm): 1.60 (3H, s), 1.68 (3H, s), 1.35-2.48 (15H, m), 2.75-2.86 (3H , m), 3.22-3.36 (IH, m), 3.48 (IH, wide s), 3.61-3.76 (IH, m), 5.03-5.08 (IH, m), 6.27 (IH, d, J = 8.0 Hz), 7.26-7.40 (3H, m), 7.55-7.58 (2H, m)

FAB-MS low resolution (m/e, (C24H34F2N2O2 + H)+): 421.

Example 3

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S)-3,3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide and (2R) -N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formulas

[image]

The title compound was prepared using (2R)-[(1S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid in the same manner as described in step 3 of Example 1 and separation in the final step.

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S,3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

1H-NMR (CDCl3, δ ppm): 1.60 (3H, s), 1.68 (3H, s), 1.31-2.33 (15H, m), 2.44-2.49 (IH , m), 2.69-2.81 (2H, m), 3.19-3.30 (IH, m), 3.62-3.74 (IH, ni), 3.90 (IH, wide s), 5.03-5.28 (2H, m), 5.87-5.91 (1H, m), 7.25-7.40 (3H, m), 7.53-7.57 ( 2H, m)

FAB-MS low resolution (m/e, (C24H35FN2O2 + H)+): 403.

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

1H-NMR (CDCl3, δ ppm): 1.61 (3H, s), 1.68 (3H, s), 1.37-2.26 (14H, m), 2.32-2.37 (2H , m), 2.75-2.90 (2H, m), 3.43-3.56 (IH, ni), 3.62-3.76 (IH, m), 5.04-5.13 (2H, m), 6.91-6.95 (1H, m), 7.23-7.35 (3H, m), 7.67-7.71 (2H, m)

FAB-MS low resolution (C24H35FN2O2 + H)+): 403.

Example 4

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3S)-3-fluorocyclopentene-2-hydroxy-2-phenylacetamide and (2R)- N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Stratum formula

[image]

The title compound was prepared using (2R)-[(1R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid in the same manner as described in step 3 of Example 1 and separation in the final step.

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

1H-NMR (CDCl3, δ ppm): 1.60 (3H, s), 1.70 (3H, s), 1.38-2.17 (14H, m), 2.27-2.32 (2H , m), 2.70-2.81 (2H, m), 3.19-3.32 (IH, m), 3.63-3.74 (IH, m), 3.93 (IH, wide s), 5.00-5.21 (2H, m), 5.96-6.02 (1H, m), 7.26-7.38 (3H, m), 7.55-7.58 ( 2H, m)

FAB-MS low resolution (m/e, (C24H35FN2O2 + H)+): 403.

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

1H-NMR (CDCl3, δ ppm): 1.60 (3H, s), 1.68 (3H, s), 1.38-2.32 (6H, m), 2.74-2.88 (2H , m), 3.41-3.52 (IH, m), 3.63-3.74 (IH, m), 5.02-5.21 (2H, m), 6.90 (IH, d , J = 8.2 Hz), 7.23-7.35 (3H, m), 7.66-7.69 (2H, m)

FAB-MS low resolution (m/e, (C24H35FN2O2 + H)+): 403.

Example 5

N-[1-[(3Z)-(4-trifluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide

To a solution of 3.51 g of 2-cyclopentyl-2-hydroxy-2-phenylacetic acid in 40 mL of N,N-dimethylformamide, 2.63 g of 1,1-carbonyldiimidazole was added and stirred at room temperature for 2 hours. 3.96 g of 4-amino-1-(t-butoxycarbonyl)-piperidine monohydrochloride, 200 mg of 4-dimethylaminopyridine and 6.9 mL of diisopropylethylamine were added to the reaction mixture, followed by stirring overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 3/1) to give 2.84 g of a white solid. The solid was dissolved in 30 mL of 10% hydrochloric acid in methanol and stirred overnight at room temperature. The solvent was distilled under reduced pressure, the residue was diluted with water and washed with diethyl ether. The aqueous layer was basified with sodium hydroxide and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure afforded 2.15 g of the title compound as a white solid.

Stage 2. Synthesis of (3Z)-4-trifluoromethyl-3-pentenyl-t-butyldiphenylsilyl ether

To a solution of 2.94 g of (3-t-butyldiphenylsilyloxypropyl)triphenylphosphonium bromide in 40 mL of tetrahydrofuran, a solution of 2.5 mL of a 1.7 M solution of n-butyllithium in hexane was added dropwise at -78°C. The temperature rose to -20°C. After stirring for 1 hour at said temperature, the reaction mixture was cooled to -78°C and 0.5 mL of trifluoroacetone was added dropwise, followed by stirring overnight until the temperature rose to room temperature. The reaction liquid was diluted with hexane, washed with 10% hydrochloric acid, water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (solvent: hexane / ethyl acetate - 9/1) to give 1.44 g of the title compound.

Stage 3. Synthesis of (3Z)-4-trifluoromethyl-3-pentenol

To a solution of 1.44 g of (3Z)-4-trifluoromethyl-3-pentenyl-butyl-diphenylsilyl ether in 8 mL of tetrahydrofuran was added 4.4 mL of a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran, followed by stirring for 2 hours at room temperature. temperature. The reaction mixture was diluted with diethyl ether, washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: ethyl acetate) to give 414 mg of the title compound.

Stage 4. Synthesis of (3Z)-4-trifluoromethyl-3-pentenyl p-toluenesulfonate

To a solution of 414 mg of (3Z)-4-trifluoromethyl-3-pentenol in 6 mL of pyridine was added 565 mg of p-toluenesulfonyl chloride under ice cooling, followed by stirring for 16 hours at room temperature. The reaction mixture was diluted with diethyl ether, washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 9/1) to give 412 mg of the title compound.

Stage 5. Synthesis of N-[1-[(3Z)-(4-trifluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

To a solution of 77 mg N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide in 3 mL N,N-dimethylformamide, 74 mg (3Z)-4-trifluoromethyl-3-pentenyl p -toluenesulfonate, 102 mg of potassium carbonate and 43 mg of potassium iodide, followed by heating under reflux for 3 hours. The reaction liquid was diluted with diethyl ether, washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced flame and the residue obtained was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (manufactured by Merck); chloroform / methanol = 9/1) to give 27 mg of the title compound as an oil.

1H-NMR (CDCl3, δ ppm): 1.12-1.88 (16H, m), 1.83 (3H, s), 2.01-2.13 (2H, m), 2.68-2 .80 (2H, m), 2.97-3.10 (IH, m), 3.13 (IH, wide s), 3.62-3.76 (IH, m), 5.65-5, 72 (IH, m), 6.32 (IH, d, J = 8.5 Hz), 7.23-7.36 (3H, m), 7.59 (2H, d, J = 7.3 Hz )

FAB-MS low resolution (m/e, (C24H33F3N2O2 + H)+): 439.

Example 6

N-[1-[(3Z)-(4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

Structural formula

[image]

the title compound was prepared by a procedure similar to steps 2-5 of Example 5, using fluoroacetone.

1H-NMR (CDCl3, δ ppm): 1.04-2.16 (14H, m), 1.79 (3H, s), 2.16-2.28 (2H, m), 2.28-2 .40 (2H, m), 2.66-2.86 (2H, m), 2.94-3.24 (2H, m), 3.62-3.78 (IH, m), 4.86 (2H, d, J = 47.5 Hz), 5.34-5.44 (IH, m), 6.36 (IH, d, J - 8.3 Hz), 7.22-7.40 ( 3H, ni), 7.56-7.64 (2H, m)

Example 7

N-[1-[(3E)-(4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of (2E)-5-bromo-2-methyl-2-pentenol

To a solution of 681 mg of selenium dioxide in 10 mL of dichloromethane, 2.5 mL of t-butyl peroxide was added at room temperature, it was stirred for 30 minutes at said temperature, and a further 2.0 g of 5-bromo-2-methyl-2-pentene was added. followed by stirring for 2 hours. The reaction mixture was diluted with diethyl ether, washed with aqueous sodium thiosulfate solution, 10% potassium hydroxide solution and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 20/1) to give 1.24 g of the title compound.

Stage 2. Synthesis of (2E)-5-bromo-2-methyl-2-pentenyl t-butyldimethylsilyl ether

To a solution of 300 mg of (2E)-5-bromo-2-methyl-2-pentenol in 10 mL of N,N-dirnethylformamide, 302 mg of t-butyldimethylsilyl chloride and 137 mg of imidazole were added, followed by stirring for 1 hour at room temperature. The reaction liquid was diluted with diethyl ether, washed with water and brine and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 604 mg of the title compound.

Step 3. N-[1-[(3E)-(4t-Butyldimethylsilyloxymethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

The title compound was prepared by a procedure similar to step 5 of Example 5, using (2E)-5-bromo-2-methyl-2-pentenyl t-butyldimethylsilyl ether.

Stage 4. Synthesis of N-[1-[(3E)-(4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

To a solution of 59 mg of tetrabutylammonium fluoride trihydrate in 3 mL of tetrahydrofuran, 200 mg of molecular sieves 4A, 31 mg of N-[l-[(3E)-(4-t-butyldimethylsilyloxymethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl -2-hydroxy-2-phenylacetamide and 22 mg of p-toluenesulfonyl fluoride, followed by heating under reflux at 80° C. overnight. After removing insolubles by filtration, the solvent was distilled off under reduced pressure. The remaining residue was purified by preparative thin-layer chromatography [Kieselgel ™ 60F254, Art 5744 (manufactured by E. Merck); chloroform / methanol = 20/1], to give 11 mg of the title compound as an oil.

1H-NMR (CDCl3, δ ppm): 1.10-1.76 (10H, m), 1.70 (3H, s), 1.76-1.95 (2H, m), 1.95-2 .42 (6H, m), 2.72-2.88 (2H, m), 2.94-3.24 (2H, m), 3.62-3.78 (IH, m), 4.69 (2H, d, J = 47.8 Hz), 5.44-5.54 (IH, m), 6.37 (IH, d, J = 8.0 Hz), 7.22-7.40 ( 3H, m), 7.56-7.64 (2H, m)

FAB-MS low resolution (m/e, (C24H35FN2O2 + H)+): 403.

Example 8

(2R)-N-(1-cycloheptylmethylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared in a manner similar to steps 1 to 5 of Example 5, using (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid and cycloheptylmethyl methanesulfonate.

1H-NMR (CDCl3, δ ppm): 1.03-2.27 (27H, m), 2.63-2.71 (2H, m), 3.21-3.33 (1H, m), 3 .49 (IH, wide s), 3.61-3.72 (IH, m), 6.23 (IH, d, J = 8.3 Hz), 7.27-7.39 (3H, m) , 7.53-7.57 (2H, m)

FAB-MS low resolution (m/e, (C26H38FN2O2 + H)+): 449.

Example 9

(2R)-N-[1-[(3E)-4-fluoromethyl-3-pentenyl]-piperidin-4-yl1-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 7, using (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

1H-NMR (CDCl3, δ ppm): 1.34-1.52 (2H, m), 1.69 (3H, s), 1.75-2.31 (12H, m), 2.31-2 .46 (2H, m), 2.72-2.86 (2H, m), 3.24-3.38 (IH, m), 3.43 (IH, broad s), 3.62-3, 78 (IH, m), 4.69 (2H, d, J = 47.8 Hz), 5.42-5.52 (IH, m), 6.34 (IH, d, J - 7.9 Hz ), 7.24-7.42 (3H, m), 7.52-7.60 (2H, m)

FAB-MS low resolution (m/e, C24H33F3N2O2, + H)+): 439.

Example 10

(2R)-N-[1-(6-methylpyridin-2-yl-methyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of (2R)-N-(piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared by a similar procedure to step 1 of Example 5, using (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

Stage 2. Synthesis of (2R)-N-[1-(6-methylpyridin-2-yl-methyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

3 μL of acetic acid was sequentially added to a solution of 17 mg of (2R)-N-(piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide in 2 mL of tetrahydrofuran, 12 mg of 6-methylpyridine-2-carbaldehyde and 21 mg of sodium triacetoxyborohydride at room temperature and stirred overnight at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Ait 5744 (Merck); chloroform / methanol = 10/1], to give 9 mg of the title compound as a solid.

1H-NMR (CDCl3, δ ppm): 1.35-1.50 (2H, m), 1.72-2.23 (10H, m), 2.53 (3H, s), 2.70-2 .80 (2H, m), 3.21-3.35 (IH, m), 3.59 (2H, s), 3.60-3.78 (IH, m), 6.31 (IH, d , J = 8.5 Hz), 7.02 (IH, t, J = 7.6 Hz), 7.18 (IH, t, J = 7.6 Hz), 7.28-7.39 (3H , m), 7.50 (IH, t, J - 7.6 Hz), 7.53-7.59 (2H, m)

Example 11

(2R)-N-[1-(3-thienylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenacetamide

Structural formula

[image]

The title compound was prepared by the method described in step 2 of Example 10 using thiopheu-3-aldehyde.

1H-NMR (CDCl3, δ ppm): 1.30-1.50 (2H, m), 1.56-2.30 (10H, m), 2.66-2.82 (2H, m), 3 .22-3.37 (IH, in), 3.40 (IH, s), 3.49 (2H, s), 3.61-3.78 (IH, m), 6.25 (IH, d , J = 8.2 Hz), 7.02 (IH, dd, J = 1.1 Hz, 7.6 Hz), 7.06-7.12 (IH, m), 7.22- 7.42 (4H, m), 7.50-7.60 (2H, m)

FAB-MS low resolution (m/e (C23H28F2N2O2S + H)+): 435.

Example 12

(2R)-N-[1-(3-furylmethyl)piperidin-4-yl]-2-[1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 2 of Example 10, using furan-3-aldehyde.

1H-NMR(CDCl3, δ ppm): 1.32-1.47 (2H, m), 1.73-2.27 (10H, m), 2.70-2.78 (2H, m), 3 ,24-3.35 (IH, ni), 3.33 (2H, s), 3.42 (IH, s), 3.62-3.75 (IH, m), 6.26 (IH, d , J = 7.2 Hz), 6.34 (1H, s), 7.27-7.40 (5H, m), 7.52-7.57 (2H, m)

FAB-MS low resolution (m/e C23H28F2N2O3 + H)+): 419.

Example 13

(2R)-N-[1-(2-furylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 2 of Example 10, using furan-2-aldehyde.

1H-NMR (CDCl3, δ ppm): 1.35-1.49 (2H, m), 1.73-2.25 (10H, m), 2.70-2.80 (2H, m), 3 .23-3.35 (IH, m), 3.48 (IH, s), 3.49 (2H, s), 3.61-3.73 (IH, m), 6.17 (IH, d , J = 3.0 Hz), 6.27-6.31 (2H, m), 7.27-7.38 (4H, m), 7.52-7.56 (2H, m)

FAB-MS low resolution (m/e C23H28F2N2O3 + H)+): 419.

Example 14

(2R)-N-[1-(2-pyridylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 2 of Example 10, using pyridine-2-aldehyde.

1H-NMR (CDCl3, δ ppm): 1.39-1.52 (2H, m), 1.75-2.25 (10H, m), 2.70-2.80 (2H, m), 3 ,24-3.36 (IH, m), 3.58 (IH, s), 3.61 (2H, s), 3.67-3.77 (IH, m), 6.32 (IH, d , J = 7.8 Hz), 7.15 (IH, ddd, J = 1.2 Hz, 4.8 Hz, 7.6 Hz), 7.27- 7.39 (4H, m), 7, 53-7.57 (2H, m), 7.63 (IH, td, J = 1.8 Hz, 7.6 Hz), 8.52 (IH, ddd, J = 1.2 Hz, 1.8 Hz, 3.0 Hz)

FAB-MS low resolution (m/e C24H29F2N3O2 + H)+): 430.

Example 15

(2R)-N-[1-(3-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

A solution of 71 mg of (2R)-N-(3-piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide in 2 mL of N,N-dimethylformamide was added 74 mg of 3-methoxybenzyl chloride and 80 mg of potassium carbonate at room temperature, followed by stirring for 12 hours. The reaction mixture was diluted with diethyl ether, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (Merck); chloroform / methanol = 9/1], to give 75 mg of the title compound as a white solid.

1H-NMR (CDCl3, δ ppm): 1.32-1.54 (2H, m), 1.65-2.30 (10H, m), 2.68-2.85 (2H, m), 3 ,21-3.39 (IH, m), 3.42 (IH, s), 3.45 (2H, s), 3.62-3.78 (IH, m), 3.80 (3H, s ), 6.27 (IH, d, J = 8.2 Hz), 6.76-6.83 (IH, m), 6.84-6.90 (2H, m), 7.21 (IH, t, J = 8.0 Hz), 7.24-7.40 (3H, m), 7.51-7.59 (2H, m)

FAB-MS low resolution (m/e (C26H32F2N2O3 + H)+): 459.

Example 16

(2R)-N-1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared in a similar manner as described in Example 15 using benzyl bromide.

1H-NMR(CDCl3, δ ppm): 1.35-1.52 (2H, m), 1.70-2.23 (10H, m), 2.70-2.81 (2H, m), 3 ,22-3.34 (IH, m), 3.41 (IH, s), 3.48 (2H, s), 3.60-3.80 (IH, m), 6.27 (IH, d , J = 8.0 Hz), 7.24-7.30 (8H, m), 7.54-7.56 (2H, m)

FAB-MS low resolution (m/e (C25H30F2N2O2 + H)+): 429.

Example 17

(2R)-N-[1-(3-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared in a similar manner as described in Example 15 using 3-fluorobenzyl chloride.

1H-NMR (CDCl3, δ ppm): 1.34-1.52 (2H, m), 1.52-2.30 (10H, m), 2.65-2.80 (2H, m), 3 ,22-3.38 (IH, m), 3.40 (IH, s), 3.72 (2H, s), 3.60-3.80 (IH, m), 6.28 (IH, d , J = 7.7 Hz), 6.88-6.97 (IH, m), 7.00-7.10 (2H, m), 7.20-7.42 (4H, m), 7, 51-7.60 (2H, m)

FAB-MS low resolution (m/e (C25H29F3N2O2 + H)+): 447.

Example 18

(2R)-N-[1-(3-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared in a similar manner as described in Example 15 using 3-chlorobenzyl chloride.

1H-NMR (CDCl3, δ ppm): 1.33-1.50 (2H, m), 1.60-2.25 (10H, m), 2.67-2.77 (2H, m), 3 ,24-3.38 (IH, m), 3.44 (2H, s), 3.63-3.76 (IH, m), 6.29 (IH, d, J = 8.0 Hz), 7.13-7.40 (7H, m), 7.53-7.57 (2H, m)

FAB-MS low resolution (m/e (C25H29ClF2N2O2 + H)+): 463.

Example 19

(2R)-N-[1-(2-thienylmethyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared in a similar manner as described in Example 15 using 2-thienylmethyl chloride.

1H-NMR (CDCl3, δ ppm): 1.32-1.50 (2H, m), 1.52-2.30 (10H, m), 2.70-2.82 (2H, m), 3 ,22-3.36 (IH, m), 3.41 (IH, s), 3.62-3.76 (IH, m), 3.68 (2H, s), 6.26 (IH, d , J = 7.9 Hz), 6.87 (IH, dd, J = 3.2 Hz, 4.8 Hz), 6.92 (IH, dd, J = 3.2 Hz, 4.8 Hz) , 7.21 (IH, dd, J = 1.5 Hz, 4.8 Hz), 7.24-7.40 (3H, m), 7.50-7.58 (2H, m)

FAB-MS low resolution (m/e (C23H28F2N2O2S + H)+): 435.

Example 20

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

Structural formula

[image]

The compound from Example 20 was prepared following procedures 1, 2 and 3.

Procedure 1:

Stage 1. Synthesis of 6-tert-butyldiphenylsilyloxymethylpyridine-2-carboxylic acid

A solution of 1.8 g of ethyl 6-hydroxymethylpyridine-2-carboxylate in 55 mL of N,N-dimethylformamide was added under ice-cooling, followed by 1.4 g of imidazole and 3.9 g of tert-butyldiphenylsilane, followed by stirring for 12 hours. at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium carbonate solution, water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure and the residue was dissolved in 60 mL of methanol. A solution of 7.5 mL of 4N aqueous sodium hydroxide solution was added, stirred for 20 hours at room temperature and for a further 2 hours at 60°C. Methanol was distilled off under reduced pressure and the residue was acidified with 1N hydrochloric acid. The system was extracted with chloroform, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4/1) to give 895 mg of the title compound as a white solid.

Stage 2. Synthesis of 6-tert-butoxycarbonylaminopyridin-2-ylmethyl tert-butyldiphenylsilyl ether

To a solution of 890 mg of 6-tert-butyldiphenylsilyloxymethylpyridine-2-carboxylic acid as obtained in step 1 in 30 mL of toluene was added sequentially 0.63 mL of triethylamine, 3.2 mL of tert-butanol, and 887 mg of diphenylphosphoryl azide at room temperature, followed by heating through 16 hours at 100°C with stirring. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium carbonate solution, 10% citric acid solution, water and then with saturated salt solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4/1) to give 863 mg of the title compound as an oily substance.

Stage 3. Synthesis of 6-tert-butyloxycarbonylaminopyridine-2-methanol

The title compound was prepared in the same manner as described in Step 3 of Example 5 using 6-tert-butyloxycarbonylaminopyridin-2-ylmethyl tert-butyldiphenylsilyl ether as obtained in Step 2.

Stage 4. Synthesis of 6-tert-butyloxycarbonylaminopyridin-2-ylmethyl methanesulfonate

To a solution of 61 mg of 6-tert-butyloxycarbonylaminopyridine-2-methanol as obtained in step 3 above in 2 mL of chloroform was added under ice-cooling 0.19 mL of triethylamine and 0.032 mL of methanesulfonyl chloride, followed by stirring for 1 hour at the same temperature. . The reaction mixture was diluted with ethyl acetate, washed with saturated sodium carbonate solution, water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 124 mg of the title compound as an oil.

Step 5. (2R)-N-[1-(6-tert-butyloxycarbonylaminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2- phenylacetamide

The title compound was prepared in the same manner as described in Example 15 using 6-tert-butyloxycarbonylaminopyridin-2-ylmethyl methanesulfonate as obtained in step 4 above.

Stage 6. Synthesis of (2R)-N-[1-(6-aminopyridin-2-ylmethylpiperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was obtained as a white solid after treating (2R)-N-[1-(6-tert-butoxycarbonylaminopyridin-2-ylmethyl)piperidine-2-hydroxy-2-phenylacetamide as obtained in step 5 above with hydrochloric acid at normal way.

1H-NMR (CD3OD, δ ppm): 1.76-2.14 (10H, m), 3.20-3.63 (5H, m), 3.85-4.00 (IH, m), 4 .44 (2H, s), 7.07-7.34 (2H, m), 7.25-7.34 (3H, m), 7.58-7.60 (2H, m), 7.89 -7.94 (IH, m)

FAB-MS low resolution (m/e (C24H30F2N4O2 + H)+): 445.

Procedure 2:

Stage 1. Synthesis of ethyl 6-tert-butyloxycarbonylaminopyridine-2-carboxylate

The title compound was prepared in the same manner as described in step 2 of procedure 1 above using 6-ethoxylcarbonylpyridine-2-carboxylic acid.

Stage 2. Synthesis of 6-tert-butyloxycarbonylaminopyridine-2-methanol

To a solution of 500 mg of calcium chloride in 10 mL of ethanol, 150 mg of sodium cyanoborohydride was added under ice-cooling, followed by stirring for 15 minutes at the same temperature. 1.1 g of ethyl 6-tert-butyloxycarbonylaminopyridine-2-carboxylate as obtained in step 1 above was added to the reaction mixture and stirred for 13 hours at room temperature. Ethanol is distilled at 112; reduced pressure and the residue was suspended in a chloroform-water mixture to remove insoluble substances. The organic part was washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. Thus, 996 mg of the title compound was obtained as a light yellow oil.

Stage 3. Synthesis of 4-tert-butyloxycarbonylamino-1-(6-tert-butyloxycarbonylaminopyridin-2-ylmethyl)piperidine

The title compound was prepared by a similar procedure to steps 4 to 5 of the above production process 1 using 6-tert-butyloxycarbonylaminopyridine-2-methanol as obtained in step 2 above and 4-tert-butyloxycarbonylaminopiperidine.

Stage 4. Synthesis of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

163 mg of 4-tert-butoxycarbonylamino-1-(6-tert-butyloxycarbonylaminopyridin-2-ylmethyl)piperidine as obtained in Step 3 above was dissolved in 5 mL of a 10% HCl solution in methanol, followed by stirring for 13 hours. at 40°C. Methanol was distilled under reduced pressure and the remaining residue was suspended in 15 mL of chloroform to which 0.16 mL of triethylamine, 86 mg of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2- hydroxy-2-phenylacetic acid, 114 mg of hydroxybenzotriazole and 75 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, followed by stirring for 1.5 hours at room temperature. The reaction mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate solution and then with saturated salt solution and dried over anhydrous magnesium sulfate. After solvent-distillation under reduced pressure, the obtained residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 50/1 to 20/1) to give 101 mg of the title compound as a white solid.

1H-NMR (CDCl3, δ ppm): 1.35-1.51 (2H, m), 1.70-2.25 (10H, m), 2.68-2.80 (2H, m), 3 ,21-3.35 (IH, m), 3.41 (2H, s), 3.52 (IH, wide s), 3.62-3.77 (IH, m),'4.40 (2H , wide s), 6.28 (IH, d, J - 8.2 Hz), 6.36 (IH, d, J - 8.2 Hz), 6.67 (IH, d, J - 7.3 Hz), 7.27-7.40 (4H, m), 7.53-7.57 (2H, m)

Stage 5. Synthesis of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

The title compound was prepared by treating (2R)-N-[1-(6-aminopyridin-2-ylmethylpiperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide with hydrochloric acid according to accepted practice.

Step 3:

Stage 1. Synthesis of 2-tert-butoxycarbonylamino-6-methylpyridine

5 g of di-tert-butyloxydicarbonate was added to a solution of 2 g of 6-methyl-2-aminopyridine in 30 mL of chloroform at room temperature. The mixture was then heated to 70°C and 2.5 g of 4-dimethylaminopyridine was added, followed by stirring for 2 hours at the same temperature. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 20/1) to give 4.1 g of the title compound as a white solid.

Stage 2. Synthesis of (2R)-N-[1-aminopyrdin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

To a solution of 100 mg of 2-tert-butyloxycarbonylamino-6-methylpyridine as obtained in step 1 above in 3 mL of carbon tetrachloride, 90 mg of N-bromosuccinimide and 10 mg of benzoyl peroxide were sequentially added, followed by heating for 6 hours at reflux with stirring. After filtering the insoluble substances, the solvent was distilled under reduced pressure. The title compound was prepared by treating the residue analogously to step 5 of procedure 1 and steps 4-5 of procedure 2.

Example 21

Synthesis of (2R)-N-[1-(6-amino-4-methoxypyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 20, using 6-hydroxymethyl-4-methoxypyridine-2-carboxylate.

1H-NMR (CD3OD, δ ppm): 1.69-2.21 (10H, m), 3.10-3.70 (5H, m), 3.83-3.97 (IH, m), 3 .98 (3H, s), 4.30-4.46 (2H, m), 6.39-6.47 (IH, m), 6.74-6.89 (IH, m), 7.20 -7.38 (3H, m), 7.58 (2H, d, J = 6.9 Hz)

FAB-MS low resolution (m/e (C25H32F2N4O3 + H)+): 475.

Example 22

Synthesis of (2R)-N-[1-(3-amino-5-methylbenzyl)piperidin-4-yl]-2-([1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

Structural formula

[image]

Stage 1. Synthesis of N-(tert-butoxycarbonyl)-3,5 dimethylaniline

To a solution of 1.2 g of 3,5-dimethylaniline in a liquid mixture of 20 mL of dioxane, 10 mL of 10% aqueous sodium hydroxide solution and 2.7 g of di-tert-butyldicarbonate were added, followed by heating for 1.5 hours at 100°C with stirring. The reaction mixture was diluted with diethyl ether, washed with water and then with saturated salt solution and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by column chromatography (solvent: hexane / ethyl acetate = 9/1) to give 1.8 g of the title compound as an oil.

Stage 2. Synthesis of 3-(tert-butyloxycarbonylamino)-5-methylbenzyl bromide

To a solution of 1.8 g of N-(tert-butyloxycarbonyl)-3,5-dimethylaniline as obtained in step 1 above in 20 mL of carbon tetrachloride was added 1.5 g of N-bromosuccinimide and 53 mg of 2,2'-azobis(isobutyronitrile) , followed by heating for 3 hours at 100°C with stirring. The reaction mixture was diluted with hexane, filtered and the solvent was distilled off under reduced pressure to give 2.8 g of the title compound as an oil.

Stage 3. Synthesis of (2R)-N-[1-(3-amino-5-methylbenzyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

The title compound was prepared by a similar procedure to steps 5-6 of production procedure 1 of Example 20 using 3-(tert-butyloxycarbonylamino)-5-methylbenzyl bromide as obtained in step 2 above.

1H-NMR (CD3OD, δ ppm): 1.66-2.11 (12H, m), 2.99-3.48 (3H, m), 3.26 (3H, s), 3.78-3 .98 (1H, m), 4.28 (2H, s), 7.18-7.60 (8H, m)

FAB-MS low resolution (m/e C26H33F2N3O2 + H)+): 458.

Example 23

Synthesis of (2R)-N-[1-(3-aminobenzyl)piperidin-4-yl]-2-[1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of (2R)-N-[1-(3-nitrobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared similarly to the procedure of Example 15 using 3-nitrobenzyl chloride.

Stage 2. Synthesis of (2R)-N-[1-(3-aminobenzylpiperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

6.5 mg of (2R)-N-[1-(3-nitrobenzylpiperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide as obtained in the above step l was heated to 60°C together with 2 mg of iron powder in aqueous ethanol. After the addition of 1 drop of conc. hydrochloric acid, heating was continued at 100°C for about 1 hour with stirring. The reaction mixture was basified with 4N aqueous sodium hydroxide and extracted with chloroform.The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 4.8 mg of the title compound as a white solid.

1H-NMR (CDCl3, δ ppm): 1.30-1.48 (2H, m), 1.50-2.25 (10H, m), 2.68-2.78 (2H, m), 3 .24-3.40 (IH, m), 3.38 (2H, s), 3.43 (IH, s), 3.52-3.80 (IH, m), 6.26 (IH, d , J = 7.9 Hz), 6.57 (IH, dd, J = 1.5 Hz, 7.8 Hz), 6.65 (IH, d, J = 1.5 Hz), 6.66 ( IH, d, J = 7.8 Hz), 7.08 (IH, t, J = 7.8 Hz), 7.28-7.39 (3H, m), 7.53-7.57 (2H , m)

FAB-MS low resolution (m/e (C25H31F2N3O2 + H)+): 444.

Example 24

Synthesis of (2R)-N-[1-(2-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

Structural formula

[image]

The title compound (free base) was obtained similarly to the procedure of Example 23 using 2-nitrobenzyl chloride, which was treated with hydrogen chloride to give the title dihydrochloride compound.

1H-NMR (CD3OD, δ ppm): 1.50-1.95 (10H, m), 2.92-3.07 (2H, m), 3.07-3.20 (1H, m), 3 .24-3.38 (2H, m), 3.67-3.80 (1H, m), 4.15-4.27 (2H, m), 7.05-7.45 (9H, m)

FAB-MS low resolution (m/e (C25H31F2N3O2 + H)+): 444.

Example 25

Synthesis of (2R)-N-[1-(4-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 23 using 4-nitrobenzyl chloride.

1H-NMR(CDCl3, δ ppm): 1.35-1.52 (2H, m), 1.70-2.23 (10H, m), 2.70-2.82 (2H, m), 3 .23-3.35 (IH, m), 3.41 (2H, s), 3.30-3.70 (3H, m), 3.65-3.75 (IH, m), 6.29 (IH, d, J = 7.4 Hz), 6.63 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz), 7.28-7 .39 (3H, m), 7.52-7.56 (2H, m)

FAB-MS low resolution (m/e C25H31F2N3O2 + H)+): 444.

Example 26

Synthesis of (2R)-N-[1-(4-amino-3-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-

phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 23 using 3-methoxy-4-nitrobenzyl chloride.

1H-NMR (CDCl3, δ ppm): 1.35-1.60 (2H, m), 1.70-2.30 (10H, m), 2.70-2.90 (2H, m), 3 ,22-3.38 (IH, m), 3.44 (2H, s), 3.40-3.60 (IH, m), 3.62-3.85 (3H, m), 3.85 (3H, s), 6.36 (IH, d, J = 7.9 Hz), 6.60-6.70 (2H, m), 6.81 (IH, s), 7.24-7, 40 (3H, m), 7.51-7.58 (2H, m)

FAB-MS low resolution (m/e (C26H33F2N3O3 + H)+): 474.

Example 27

Synthesis of (2R)-N-[1-(3,5-diaminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 23 using 3,5-dinitrobenzyl chloride.

1H-NMR (CDCl3, δ ppm): 1.30-2.20 (12H, m), 2.70-2.80 (2H, m), 3.23-3.36 (1H, m), 3 .28 (2H, s), 3.44 (IH, s), 3.60-3.73 (IH, m), 5.93 (IH, d, J - 2.0 Hz), 6.07 ( 2H, d, J = 2.0 Hz), 6.23 (IH, d, J = 7.5 Hz), 7.29-7.40 (3H, m), 7.53-7.57 (2H , m)

FAB-MS low resolution (m/e (C25H32F2N4O2 + H)+): 459.

Example 28

Synthesis of (2R)-N-[1-(5-methylfuran-2-imethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of 4-(tert-butyloxycarbonylamino)-1-(5-methyl-2-furylmethylpiperidine)

To a solution of 200 mg of 4-(tert-butyloxycarbonylamino)piperidine in 5 mL of tetrahydrofuran was added 0.1 mL of 5-methylfuran-3-aldehyde, 0.06 mL of acetic acid, and 318 mg of sodium triacetoxyborohydride at room temperature, followed by stirring for 12 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After distillation of the solvent under reduced pressure, the residue was recrystallized from ethyl acetate/n-hexane to give 198 mg of the title compound.

Stage 2. Synthesis of (2R)-N-[1-(S-methyl-2-furylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-

phenylacetamide

To 88 mg of 4-(tert-butoxycarbonylamino)-1-(5-methyl-2-furylmethyl)piperidine as obtained in Step 1 above, 2 mL of a 10% solution of hydrogen chloride in methanol was added at room temperature, followed by mixing for about 12 hours. The solvent was distilled under reduced pressure and 59 mg of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid, 93 mg of hydroxybenztriazole, 0.2 mL of triethylamine and 6 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide at room temperature, followed by stirring for 2 hours. After addition of water, the reaction mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 50/1) to give 63 mg of the title compound as a white solid.

1H-NMR (CDCl3, δ ppm): 1.35-1.54 (2H, m), 1.60-2.25 (10H, m), 2.27 (3H, s), 2.71-2 .86 (2H, m), 3.22-3.36 (IH, m), 3.40 (IH, s), 3.45 (2H, s), 3.60-3.76 (IH, m ), 5.85-5.90 (IH, m), 6.05 (2H, d, J = 3.0 Hz), 6.25 (IH, d, J = 7.9 Hz), 7.26 -7.40 (3H, m), 7.50-7.56 (2H, m)

FAB-MS low resolution (m/e (C24H30F2N2O3 + H)+): 433.

Example 29

Synthesis of (2R)-N-[1-(3-methylbenzyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of 4-(tert-butyloxycarbonylamino)-1-(3-methylbenzyl)piperidine

The title compound was prepared by a similar procedure to Example 15 using 4-(tert-butyloxycarbonylamino)piperidine and 3-methylbenzyl bromide.

Stage 2. Synthesis of (2R)-N-[(1-3-methylbenzylpiperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared by a similar procedure to Example 28 using 4-(tert-butyloxycarbonylamino)-1-(3-methylbenzyl)piperidine as obtained in step 1 above.

1H-NMR (CDCl3, δ ppm): 1.24-1.50 (2H, m), 1.50-2.25 (10H, m), 2.33 (3H, s), 2.60-2 .82 (2H, m), 3.20-3.55 (3H, m), 3.42 (2H, s), 6.25 (IH, d, J = 8.1 Hz), 7.00- 7.14 (3H, m), 7.19 (IH, t, J = 7.6 Hz), 7.23-7.42 (3H, m), 7.50-7.60 (2H, m)

FAB-MS low resolution (m/e (C26H32F2N2O2 + H)+): 443.

Example 30

Synthesis of (2R)-N-[1-(4-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 2 of Example 10 using p-anisaldehyde.

1H-NMR (CDCl3, δ ppm): 1.32-1.47 (2H, m), 1.75-2.23 (10H, m), 2.65-2.76 (2H, m), 3 ,22-3.36 (IH, m), 3.42 (2H, s), 3.46 (IH, s), 3.63-3.76 (IH, m), 3.79 (3H, s ), 6.27 (IH, d, J = 8.2 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.28-7.39 (3H, m), 7.52-7.56 (2H, m)

FAB-MS low resolution (m/e (C26H32F2N2O3 + H)+): 459.

Example 31

Synthesis of (2R)-N-[1-(3-amino-5-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

Structural formula

[image]

Stage 1. Synthesis of methyl 3-tert-butoxycarbonylarrimo-5-methoxybenzoate

To a solution of 864 mg of methyl 3-methoxy-5-nitrobenzoate in 15 mL of methanol was added 1.0 g of di-tert-butyl dicarbonate and 912 mg of 10% palladium on charcoal, followed by stirring for 7 hours at room temperature in hydrogen atmosphere. The reaction liquid was filtered through celite. Distillation of the solvent under reduced pressure afforded 1.28 g of the title compound as a white solid.

Stage 2. Synthesis of 3-tert-butoxycarbonylamino-5-methoxybenzyl alcohol

To a solution of 1.28 g of methyl 3-tert-butoxycarbonylamino-5-methoxybenzoate as obtained in step 1 above in 8 mL of toluene was added 12.1 mL of a 1.0 M solution of diisobutylaluminum hydride in tetrahydrofuran at -78°C, followed by stirring. for 1 hour at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. After distillation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 7/3) to give 262 mg of the title compound as an oil.

Stage 3. Synthesis of 3-tert-butoxycarbonylamino-5-methoxybenzaldehyde

To a solution of 194 mg of 3-tert-butoxycarbonylamino-5-methoxybenzyl alcohol as obtained in Step 2 above in 10 mL of chloroform was added 1.89 g of manganese dioxide at room temperature, followed by stirring for 2 hours. The reaction mixture was filtered through celite. Distillation of the solvent under reduced pressure gave 132 mg of the title compound as an oily substance.

Stage 4. Synthesis of (2R)-N-[1-(3-amino-5-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride

The title compound was prepared by a similar procedure to step 2 of Example 10 and step 6 of procedure 1 of Example 20 using 3-tert-butoxycarbonylamino-5-methoxybenzaldehyde as obtained in step 3.

1H-NMR (CD3OD, δ ppm): 1.74-2.14 (10H, m), 3.00-3.15 (2H, m), 3.27-3.52 (3H, m), 3 .82-3.92 (IH, m), 3.89 (3H, s), 4.32 (2H, s), 7.01 (IH, s), 7.18-7.35 (5H, m ), 7.56-7.60 (2H, m)

FAB-MS low resolution (m/e (C26H33F2N3O3 + H)+): 474.

Example 32

Synthesis of (2R)-N-[1-(4-amino-3-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 22 using 3-fluoro-4-aminotoluene.

1H-NMR (CDCl3, δ ppm): 1.28-1.50 (2H, m), 1.50-2.32 (10H, m), 2.60-2.80 (2H, m), 3 ,20-3.38 (IH, m), 3.33 (2H, s), 3.45 (IH, s), 3.55-3.76 (3H, m), 6.25 (IH, d , J = 8.2 Hz), 6.69 (IH, dd, J = 8.1, 8.9 Hz), 6.82 (IH, dd, J - 1.6, 8.1 Hz), 6 .93 (IH, dd, J = 1.6, 12.0 Hz), 7.24-7.40 (3H, m), 7.50-7.58 (2H, m)

FAB-MS low resolution (m/e, (C25H30F3N3O2 + H)+): 462.

Example 33

Synthesis of (2R)-N-[1-(6-amino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-

phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of 6-chloromethyl-4-methyl-2-acetyl-aminopyridine

To a solution of 23 mg of 6-acetylamino-4-methylpyridine-2-methanol in 2 mL of chloroform was added 0.05 mL of thionyl chloride at room temperature, followed by heating for 15 minutes with stirring under reflux. Distillation of the solvent under reduced pressure afforded the title compound.

Stage 2. Synthesis of (2R)-N-[1-(6-acetylamino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2 -phenylacetamide

The title compound was prepared by a similar procedure to Example 15 using 6-chloromethyl-4-methyl-2-acetylaminopyridine as obtained in step 1 above.

Stage 3. Synthesis of (2R)-N-[1-(6-amino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy -2-phenylacetamide

Solutions 16.5 mg (2R)-N-[1-(6-acetylamino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2- of hydroxy-2-phenylacetamide as obtained in the above step 2 in 1 mL of methanol was added 0.5 mL of 3M aqueous sodium hydroxide solution and stirred for 1.5 hours at 60°C. The reaction liquid was diluted with diethyl ether, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue obtained was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (Merck); solvent: chloroform / methanol = 10/l] to give 14 mg of the title compound as an oily substance

1H-NMR (CDCl3, δ ppm): 1.30-1.50 (2H, m), 1.71-2.30 (10H, m), 2.33 (3H, s), 2.62-2 .76 (2H, m), 3.21-3.38 (IH, m), 3.29 (2H, s), 3.60-3.78 (IH, m), 4.35-4.51 (2H, m), 6.26 (IH, s), 6.35 (IH, d, J = 8.1 Hz), 6.45 (IH, s), 7.25-7.40 (3H, m), 7.52-7.60 (2H, m)

FAB-MS low resolution (m/e, (C25H32F2N4O2 + H)+): 459.

Example 34

Synthesis of (2R)-N-[1-(3-amino-4-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

dihydrochloride

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 22 using 2-fluoro-5-methylaniline.

1H-NMR (CD3OD, δ ppm): 1.68-2.11 (10H, m), 3.00-3.50 (5H, m), 3.79-3.90 (IH, m), 4 .32 (2H, s), 6.26 (IH, s), 7.18-7.30 (3H, m), 7.43 (IH, d, J = 8.4 Hz), 7.52- 7.56 (IH, m), 7.57-7.65 (IH, m), 7.73-7.78 (IH, m)

FAB-MS low resolution (m/e, (C25H30F3N3O2 + H)+): 462.

Example 35

(2R)-N-[1-(5-amino-2-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to Example 22 and Example 23 using 2-fluoro-5-nitrotoluene.

1H-NMR (CDCl3, δ ppm): 1.36-1.49 (2H, m), 1.57-2.26 (10H, m), 2.71-2.78 (2H, m), 3 ,24-3.36 (IH, m), 3.42-3.57 (5H, m), 3.66-3.75 (IH, m), 6.24 (IH, d, J = 8, 1 Hz), 6.51-6.56 (IH, m), 6.65-6.68 (IH, m), 6.82 (IH, t, J = 9.0 Hz), 7.29- 7.40 (3H, m), 7.53-7.57 (2H, m)

FAB-MS low resolution (m/e, (C25H30F3N3O2 + H)+): 462.

Example 36

(2R)-N-[1-(2-amino-4-chloropyridin-6-ylmethyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to procedure 2 of Example 20 using 4-chloro-6-hydroxymethylpyridine-2-carboxylate.

1H-NMR (CDCl3, δ ppm): 1.42-1.54 (2H, m), 1.78-2.26 (10H, m), 2.76-2.79 (2H, m), 3 .28-3.38 (1H, m), 3.42-3.47 (3H, m), 3.67-3.75 (1H, m), 4.53-4.56 (2H, m) , 6.36 (IH, d, J = 7.2 Hz), 6.38 (IH, d, J = 1.6 Hz), 6.72 (IH, d, J = 1.6 Hz), 7 .25-7.39 (3H, m), 7.53-7.57 (2H, m)

FAB-MS low resolution (m/e, (C24H29ClF2N4O2 + H)+): 479.

Example 37

(2R)-N-[1-(3-amino-5-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

Stage 1. Synthesis of 3-chloro-5-nitrobenzyl methanesulfonate

To a solution of 92 mg of 3-chloro-5-nitrobenzyl alcohol in 3 mL of chloroform, 0.3 mL of triethylamine and 0.1 mL of methanesulfonyl chloride were added at room temperature, followed by stirring for 40 minutes, addition of a saturated aqueous sodium bicarbonate solution, and further stirring in 30 minutes. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate solution and then with saturated salt solution and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure afforded 119 mg of the title compound as an oil.

Stage 2. Synthesis of (2R)-N-[1-(3-amino-5-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was obtained by a similar procedure to Example 23 using 3-chloro-5-nitrobenzyl methanesulfonate as obtained in step 1 above.

1H-NMR (CDCl3, 5 ppm): 1.30-1.44 (2H, m), 1.73-2.22 (10H, m), 2.68-2.73 (2H, m), 3 ,24-3.36 (IH, m), 3.32 (2H, s), 3.44 (IH, wide s), 3.61-3.77 (3H, m), 6.28 (IH, d, J = 8.4 Hz), 6.49 (IH, d, J = 1.9 Hz), 6.55 (IH, dd, J - 1.7, 1.9 Hz), 6.66 ( IH, d, J = 1.7 Hz), 7.29-7.39 (3H, m), 7.53-7.56 (2H, m)

FAB-MS low resolution (m/e, (C25H30ClF2N3O2 + H)+): 459.

Example 38

(2R)-N-[1-(4-amino-3,5-difluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 2 of Example 10 using 4-amino-3,5-difluorobenzaldehyde.

1H-NMR (CDCl3, δ ppm): 1.24-2.22 (12H, m), 2.66-2.72 (2H, m), 3.27-3.41 (4H, m), 3 ,66-3.71 (3H, m), 6.28 (IH, d, J - 7.8 Hz), 6.77 (2H, d, J = 8.3 Hz), 7.28-7, 39 (3H, m), 7.54-7.56 (2H, m)

FAB-MS low resolution (m/e, (C25H29F4N3O2 + H)+): 480.

Example 39

(2R)-N-[1-(benzimidazol-5-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 2 of Example 10 using benzimidazole-5-carbaldehyde.

1H-NMR (CD3OD, δ ppm): 1.45-2.25 (10H, m), 2.25-2.48 (2H, m), 2.90-3.10 (2H, m), 3 ,20-3.42 (IH, m), 3.56-3.75 (IH, m), 3.82 (2H, s), 7.18-7.40 (4H, m), 7.51 -7.75 (4H, m), 8.17 (IH, s)

FAB-MS low resolution (m/e, (C26H30F2N4O2 + H)+): 469.

Example 40

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3.3-difluorocyclobutyl]-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 4 of procedure 2 of Example 20 using (2R)-(3,3-difluorocyclobutyl)-2-hydroxyphenylacetic acid and 4-amino-1-(6-aminopyridin-2-ylmethyl)piperidine trihydrochloride.

1H-NMR (CDCl3, δ ppm): 1.20-1.52 (2H, m), 1.60-1.86 (2H, m), 2.08-2.22 (2H, m), 2 .40-2.82 (6H, m), 3.07-3.21 (IH, m), 3.41 (2H, s), 3.60-3.80 (IH, m), 3.84 (IH, wide s), 4.40 (2H, wide s), 6.01 (IH, d, J = 8.1 Hz), 6.36 (IH, d, J = 8.2 Hz), 6 .66 (IH, d, J = 8.2 Hz), 7.28-7.42 (4H, m), 7.43-7.50 (2H, m)

FAB-MS low resolution (m/e, (C23H28F2N4O2 + H)+): 431.

Example 41

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-4,4difluorocyclohexyl)-2-hydroxy-2-phenylacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to step 4 of procedure 2 of Example 20 using (2R)-(4,4-difluorocyclohexyl-2-hydroxyphenylacetic acid) and 4-amino-1-(6-aminopyridin-2-ylmethyl)piperidine trihydrochloride.

1H-NMR(CDCl3, δ ppm): 1.20-1.97 (10H, m), 1.97-2.22 (4H, m), 2.44-2.68 (1H, m), 2 .70-2.92 (3H, m), 3.42 (2H, s), 3.62-3.80 (IH, m), 4.42 (2H, broad s), 6.36 (IH, d, J = 8.2 Hz), 6.62 (IH, d, J = 7.9 Hz), 6.67 (IH, d, J = 8.2 Hz), 7.24-7.42 ( 4H, m), 7.55-7.62 (2H, m)

FAB-MS low resolution (m/e, (C25H32F2N4O2 + H)+): 459.

Example 42

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-(4-fluorophenyl)-2-hydroxyacetamide

Structural formula

[image]

The title compound was prepared by a similar procedure to procedure 1 of Example 20 using (2R)-(3,3-difluorocyclopentyl)-2-(4-fluorophenyl)-2-hydroxyacetic acid.

1H-NMR (CDCl3, δ ppm): 1.39-1.55 (2H, m), 1.70-2.22 (10H, m), 2.73-2.81 (2H, m), 3 .23-3.36 (IH, m), 3.43 2H, s), 3.65-3.77 (IH, m), 4.43 (2H, wide s), 6.31 (IH, d , J = 7.6 Hz), 6.37 (IH, d, J = 8.2 Hz), 6.67 (IH, d, J = 7.4 Hz), 7.01-7.08 (2H , m), 7.37 (IH, dd, J = 7.4, 8.2 Hz), 7.51-7.58 (2H, m)

FAB-MS low resolution (m/e, C24H29F3N4O2 + H)+): 463.

Reference Example 1

(2R)-[(1R)-3-oxocyclopentyl]-2-hydroxy-2-phenylacetic acid

Stage 1. Synthesis of (2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one and (2R,5R)-2- (t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

Mixtures 510 mg of (2R,5R)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-one, which was synthesized according to the procedure of D. Seebach et al. [Tetrahedron. Vol. 40, p. 1313-1324 (1984)] to 20 mL of tetrahydrofuran and 1 mL of hexamethylphosphoric triamide was added 1.7 mL of a 1.5 M solution of lithium diisopropylamide in hexane at -78°C, followed by stirring for 30 minutes. Then a solution of 285 mg of cyclopentenone in 1.5 mL of tetrahydrofuran was added and the reaction mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and then with saturated salt solution and dried over magnesium sulfate.

The solvent was distilled under reduced pressure and the obtained residue was purified by chromatography on a medium pressure silica gel column (solvent: hexane / ethyl acetate = 15/1 - 10/1). Thus, 150 mg and 254 mg of the title compound were obtained as an oil. The configuration of each compound was determined from NOE NMR.

Stage 2. Synthesis of (2R)-[(1R)-3-oxocyclopentyl]-2-hydroxy-2-phenylacetic acid

1 mL was added to a solution of 61 mg of (2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one in 3 mL of methanol. 1N aqueous sodium hydroxide solution, followed by stirring for 3 hours at room temperature. Methanol was distilled off under reduced pressure and the residue was diluted with water and washed with diethyl ether. The aqueous portion was acidified with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate to give 48 mg of the title compound.

Reference Example 2

(2R)-[(1R)-3-oxocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared similarly to the procedure according to step 2 of Reference Example 1 using (2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolane-4 -she.

Reference Example 3

(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

Stage 1. Synthesis of (2R.5RV2-(t-butyT)-5-\(1RV3.3-difluorocyclopentyl]-5-phenyl-1.3-dioxolan-4-one

A solution of 256 mg of (2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one in 3 mL of chloroform was added with cooling with ice 0.34 mL of diethylaminosulfur trifluoride, followed by stirring for 20 hours at room temperature. The reaction mixture was diluted with diethyl ether, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 20/1) to give 115 mg of the title compound.

Stage 2. Synthesis of (2R)-[(1R)-3-oxocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to step 2 of Reference Example 1 using (2R,5R)-2-(t-butyl)-5-[(1R)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxolane -4-she.

Reference Example 4

(2R)-[(1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to Reference Application 3 using (2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one .

Reference Example 5

(2R)-[(1S)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid

Stage 1. Synthesis of (2R,5R)-2-(t-butyl)-5-[(1S)-3-hydroxycyclopentyl]-5-phenyl-1,3-dioxolan-4-one

A solution of 169 mg of (2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one in 2 mL of methanol was added with cooling with ice 71 mg of sodium borohydride, followed by stirring for 30 minutes at the same temperature. The reaction mixture was diluted with diethyl ether, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 157 mg of the title compound as a colorless oil.

Stage 2. Synthesis of (2R)-[(1S)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to step 2 of Reference Example 1 using (2R,5R)-2-(t-butyl)-5-[(1S)-3-hydroxycyclopentyl]-5-phenyl-1,3-dioxolane-4 -she.

Reference Example 6

(2R)-[(1R)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to Reference Example 5 using (2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one .

Reference Example 7

(2R)-[(1S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to Reference Example 3 using (2R)-[(1S)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid.

Reference Example 8

(2R)-[(1R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to Reference Example 3 using (2R)-[(1R)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid.

Reference Example 9

2-cyclopentyl-2-hydroxy-2-phenylacetic acid

To a solution of 23.5 g of ethyl phenylglyoxalate in 200 mL of tetrahydrofuran, 70 mL of a 2.0 M solution of cyclopentylmagnesium chloride in diethyl ether was added under cooling with ice, followed by stirring for 30 minutes at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 30/1 - 20/1) to give 11 g of ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate, which dissolved in 40 mL of methanol. 20 mL of 4N sodium hydroxide solution was added to the solution at room temperature, followed by stirring for 2 hours at the same temperature and further for 1 hour at 50°C. After distillation of methanol under reduced pressure, the aqueous layer was slightly acidified with 4N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was washed with a 1:1 mixture of diethyl ether and hexane. Thus, 8.7 g of the title compound were obtained.

Reference Example 10

(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

Stage 1. Synthesis of (2R.5R)-2-(t-butyl)-5-[(1S.2R.5R6S.7R)-3-oxotricyclo[5.2.1.02,6]dec-8-en-5-yl ]-5-phenyl-1,3-dioxolan-4-one

To a solution of 32 g of (2R,5R)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-one in 1.1 L of tetrahydrofuran was added 105 mL of a 1.5 M solution of lithium diisopropylamide in hexane at -78°C, followed by stirring for 30 minutes, addition of 23.4 g of (1S,2R,6S,7R)-tricyclo[5.2.1.02,6]dec-4,8-dien-3-one as dissolved in 300 mL of tetrahydrofuran, and further stirring for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane-ethyl acetate. Thus, 36.9 g of the title compound were obtained as a white solid.

Stage 2. Synthesis of (2R,5R)-2-(t-butyl)-5-[(1S)-4-oxo-2-cyclopentyl]-5-phenyl-1,3-dioxolan-4-one

Solution 25.6 g (2R,5R)-2-(t-butyl)-5-[(1S,2R,5R,6S,7R)-3-oxo-8-tricyclo[5.2.1.02,6]dec- 8-en-5-yl]-5-phenyl-1,3-dioxolan-4-one as obtained in step 1 above in 350 mL of 1,2-dichlorobenzene was heated at 175°C for 7 hours with stirring under atmosphere nitrogen. The resulting solid was collected by filtration and washed with hexane to give 14 g of the title compound as a white solid.

Stage 3. Synthesis of (2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

Solutions of 19.1 g of (2R,5R)-2-(t-butyl)-5-[(1S)-4-oxo-2-cyclopentyl]-5-phenyl-1,3-dioxolan-4-one as obtained in step 2 above to 700 mL of ethyl acetate was added 2.0 g of 10% palladium on charcoal, followed by stirring for 2 hours at room temperature under a hydrogen atmosphere. After filtration of the catalyst and distillation of the solvent under reduced pressure, the residue was recrystallized from hexane-ethyl acetate to give 14 g of the title compound as a white solid.

Stage 4. Synthesis of (2R)-[1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to Reference Example 3 using (2R,5R)-2-(t-butyl)-5-[(1R)-4-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one as obtained in step 3.

Reference Example 11

(2R)-(3,3-difluorocyclopentyl)-2-(4-fluorophenyl)-2-hydroxyacetic acid

The title compound was prepared similarly to the procedure according to step 1 of Reference Example 1 and Reference Example 3 using (R)-4-fluoromandelic acid.

Reference Example 12

(2R)-(3,3-Difluorocyclobutyl)-2-hydroxy-2-phenylacetic acid

Stage 1. Synthesis of (2R,5R)-2-(t-butyl)-5-(3-benzyloxy-1-hydroxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one

The title compound was prepared by a similar procedure to step 1 of Reference Example 1 using 3-benzyloxycyclobutanone.

Stage 2. Synthesis of (2R,5R)-2-(t-butyl)-5-(3-benzdloxycyclobutyl5-phenyl-1,3-dioxolan-4-one)

Solutions of 2.82 g of (2R,5R)-2-(t-butyl)-5-(3-benzyloxy-1-hydroxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one as obtained in step 1 above, 2.6 g of 4-dimethylaminopyridine was added to 80 mL of chloroform under ice-cooling, followed by stirring for 1 hour at the same temperature. 1 mL of methyl chloroglyoxylate was added to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was diluted with chloroform, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. After distillation of the solvent under reduced pressure, the residue was mixed with a hexane/ethyl acetate = 1/1 liquid mixture and filtered through a silica gel column. After distillation of the solvent under reduced pressure, the residue was dissolved in 80 mL of toluene and 56 mg of 2,2'-azobis(isobutyronitrile) and 2.3 mL of tri-n-butyltin hydride were added to the solution, followed by heating for 4 hours at 110 °C with stirring.

The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 8/1) to give 1.82 g of the title compound as an oily substance.

Stage 3. Synthesis of (2R, 5R)-2-(t-butyl)-5-(3-oxocyclobutyl)-5-phenyl-1.3-dioxolan-4-one

Solutions of 1.82 g of (2R,5R)-2-(t-butyl)-5-(3-benzyloxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one as obtained in step 2 above in 40 mL of ethanol, 430 mg of palladium hydroxide on charcoal was added, followed by stirring for 6 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite. After distillation of the solvent under reduced pressure, the residue was dissolved in 5 mL of dichloromethane and the resulting solution was added dropwise at -78°C to the reaction mixture formed by adding 0.63 mL of oxalyl chloride to 1.1 mL of dimethylsulfoxide in 50 mL of dichloromethane at -78°C. with stirring for 5 minutes. After stirring for 15 minutes at the same temperature, 0.5 mL of triethylamine was added to the reaction mixture and stirred for 30 minutes until the temperature rose to room temperature. The reaction liquid was diluted with chloroform, washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 8/1) to give 1.36 g of the title compound as an oily substance.

Stage 4. Synthesis of (2R)-(3,3-difluorocyclobutyl)-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a similar procedure to Reference Example 3 using (2R,5R)-2-(t-butyl)-5-(3-oxocyclobutyl)-5-phenyl-1,3-dioxolan-4-one as obtained in level 3 above.

Reference Example 13

(2R)-(4,4-Difluorocyclohexyl)-2-hydroxy-2-phenylacetic acid

Stage 1. Synthesis of (2R,5R)-2-(t-butyl)-5-(1,4-dioxaspiro[4,5]-dec-8-yl)-5-phenyl-1,3-dioxolan-4-one

The title compound was prepared by a similar procedure to Steps 1 and 2 of Reference Example 12 using 1,4-dioxa-8-oxospiro[4.5]decane.

Stage 2. Synthesis of (2R,5R)-2-(t-butyl)-5-(4-oxocyclohexyl)-5-phenyl-1,3-dioxolan-4-one

Solutions of 83 mg of (2R,5R)-2-(t-butyl)-5-(1,4-dioxaspiro[4.5]-dec-8-yl)-5-phenyl-1,3-dioxolan-4-one in 52 mg of p-toluenesulfonic acid was added to a mixture of 4 mL of acetone and 0.4 mL of water at room temperature, followed by stirring for 13 hours at 50°C. After distillation of acetone under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and then with saturated salt solution and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 70 mg of the title compound as an oil.

Stage 3. Synthesis of (2R)-(4,4-difluorocyclohexyl)-2-hydroxyphenylacetic acid

The title compound was prepared by a similar procedure to Reference Example 3 using (2R,5R)-2-(t-butyl)-5-(4-oxocyclohexyl)-5-phenyl-1,3-dioxolan-4-one.

Reference Example 14

(2R)-[(1R)-(3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

Stage 1. Synthesis of (2R.5RV2-(t-butyl)-5-[(1R)-3-hydroxymunocyclopentyl]-5-phenyl-1.3-dioxolan-4-one

To a solution of 46 mg of (2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one in 1.5 mL of pyridine was added 85 mg of hydroxylamine hydrochloride and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 55 mg of the title compound.

Stage 2. Synthesis of (2R,5R)-2-(t-butyl-5)-[(1R)-3,3-difluorocyclopentuyl-5-phenyl-1,3-dioxolan-4-one

A solution of 34 mg of (2R,5R)-2-(t-butyl)-5-[(1R)-3-hydroxyiminocyclopentyl]-5 was added to a mixture of 20 mg of nitroso tetrafluoroborate and 0.5 mL of 70% hydrogen fluoride-pyridine. -phenyl-1,3-dioxolan-4-one in 0.5 mL of dichloromethane under ice cooling. The mixture was stirred for 10 minutes at 0°C and 5 hours at room temperature. Water was added to the reaction mixture under ice cooling and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 35 mg of the title compound.

Step 3. (2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared similarly to the procedure according to step 2 of Reference Example 1 using (2R,5R)-2-(t-butyl)-5-[(1R)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxolane -4-she.

Industrial use

The fluorine-containing 1,4-disubstituted piperidine derivatives of the present invention not only have strong antagonistic activity at muscarinic M3 receptors but also have few side effects. Furthermore, they show excellent oral activity, duration of action and pharmacokinetics. This is why they are very useful in the treatment and prevention of such respiratory diseases as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable stomach syndrome, ulcerative colitis, diverticulitis and contraction of the smooth muscles of the digestive system accompanied by pain; urinary disorders such as urinary incontinence and frequency of neurogenic pollachirea, neurogenic bladder, nocturnal enuresis, inconstant bladder, cystospasm and chronic cystitis; and motion sickness.

Claims (19)

1. New derivatives of 1,4-disubstituted piperidines containing fluorine, indicated by the fact that they are represented by the general formula [I] [image] and their pharmaceutically acceptable salts, where: Ar represents an aryl group or a heteroaryl group having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (any 1 to 3 hydrogen atoms on the ring of said aryl or heteroaryl group can be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino); R1 represents C3-C6 cycloalkyl any of the 1-4 hydrogen atoms may be substituted with fluorine atom(s); R2 represents a C3-C15 saturated or unsaturated aliphatic hydrocarbon group of which any of 1 to 6 hydrogen atoms may be substituted with fluorine atom(s), an aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl group having 1 to 2 hetero atoms selected from the group consisting of consists of nitrogen, oxygen and sulfur (optionally any of 1 to 3 hydrogen atoms on the ring in said aralkyl, arylalkenyl, heteroarylalkyl and heteroarylalkenyl group can be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen , lower alkoxy, amino or lower alkylamino); and X is O or NH, ensuring that at least one of R1 and R2 contains one or more fluorine atoms. 2. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized by the fact that in them Ar is a phenyl group that can be substituted with 1 to 3 substituents selected from the group consisting of lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl , halogen, lower alkoxy, amino and alkylamino. 3. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized in that in them R1 is C3-C6 cycloalkyl in which any of 1 to 4 hydrogen atoms are substituted with fluorine atom(s). 4. Their compounds and their pharmaceutically acceptable salts according to Claim 1, characterized in that R1 in them is cyclobutyl, cyclopentyl, cyclohexyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl, 2,2,-difluorocyclopentyl, 3,3-difluorocyclopentyl, 2,2,3,3-tetrafluoro cyclopentyl, 3,3,4,4-tetrafluorocyclopentyl, 2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl , 2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl or 4,4-difluorocyclohexyl. 5. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized in that R1 in them is 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl, 2,2 ,-difluorocyclopentyl, 3,3-difluorocyclopentyl, 2,2,3,3-tetrafluorocyclopentyl, 3,3,4,4-tetrafluorocyclopentyl, 2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 2,2-difluorocyclohexyl, 3, 3-difluorocyclohexyl or 4,4-difluorocyclohexyl. 6. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized in that X is NH. 7. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized in that in them R2 is a group whose any 1 to 6 hydrogen atoms can be substituted with fluorine atom(s) and which is represented by the formula below: [image] [where Q represents methylene, ethylene, trimethylene or tetramethylene; Ra and Rc each represent a hydrogen atom or together form a single bond; and Rb, Rd and Re can be the same or different and each represents a hydrogen atom, a lower alkyl group, a C3-C8 cycloalkyl or cycloalkenyl group, or Rb, Rd, or Rd and Re together form each C3-C8 cycloalkyl or cycloalkenyl]. 8. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized in that in them R2 C5-C15 is straight chain or branched alkyl, alkenyl, alkynyl, cycloalkylalkyl or cycloalkylalkenyl in which any hydrogen atom(s) on the cycloalkyl ring can be substituted with lower alkyl; and cycloalkenylalkyl or cycloalkenylalkenyl wherein any hydrogen atom(s) on the cycloalkenyl ring may be substituted with lower alkyl; cycloalkylalkynyl, cycloalkenylalkenyl; or those in which any of 1 to 6 hydrogen atoms are substituted with fluorine atom(s). 9. Compounds or their pharmaceutically acceptable salts according to Claim 1, indicated by the fact that in them R2 is benzyl, phenethyl, phenylpropyl, phenylpropenyl, 2-pyridylmethyl, 2-pyridylethyl, 2-pyridylpropyl, 3-pyridihnethyl, 4-pyridylmethyl, 2- thiazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazoylmethyl, 2-imidazolylmethyl, 4-imidazolmethyl, 3-pyrazolmethyl, 4-pyrazolylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyrroylmethyl, 3-pyrimidinylmethyl, 4-pyrimidinylmethyl, 5-pyrimidinylmethyl, pyrazinylmethyl, 3-pyridazinylmethyl, 4-pyridazinyl, 2-benzothienylmethyl or 2-indolemethyl (any of 1 to 3 hydrogen atoms on the ring of said benzyl, phenethyl, phenylpropyl, phenylpropenyl or heteroarylalkyl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitto, lower alkoxycarbonyl, halogen, lower alkoxy, amino and lower aholamino). 10. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized in that R1 is 3,3-difluorocyclopentyl and R2 is 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyridylmethyl or benzyl ( any of the 1 to 3 hydrogen atoms on the thienyl, furylmethyl, pyridylmethyl or benzyl ring may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino). 11. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized by the fact that in them the compound is represented by the general formula [I]: (2R)-N-[1-4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S,3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-methyl-3-pentenn)piperidin-4-yl]-2-[(1R,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide N-[1-[(3Z)-(4-trifluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide N-[1-[(3Z)-(4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide N-[1-[(3E)-(4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide (2R)-N-(1-cycloheptylmethylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-[(3E)-4-fluoromethyl-3-pentenyl]-piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2- phenylacetamide (2R)-N-[1-(6-methylpyridin-2-yl-methyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-thienylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[H3-furylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2 hydroxy-2-phenylacetamide (2R)-N-[1-(2-furylmethyl)piperidin-4-yl]-2-[(1R)-3β-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[2-pyridylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopenta]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2 hydroxy-2-phenylacetamide (2R)-N-(1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-fluorobenzyl)piperidine-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopenta]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(2-thienylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride (2R)-N-[1-(6-amino-4-methoxypyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride (2R)-N-[1-(3-amino-5-methylbenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride (2R)-N-[1-(3-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(2-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dihydrochloride (2R)-N-[1-(4-aminobenza)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-amino-3-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3,5-diaminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(5-methylfuran-2-ylmethyl)piperidin-4-n]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-methylbenzyl)piperidin-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-Methoxybenzyl)piperidin-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-amino-5-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide dilyhydrochloride (2R)-N-[1-(4-amino-3-fluorobenzyl)piperidine-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-amino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-amino-4-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-bihydroxy-2-phenylacetamide dihydrochloride (2R)-N-[1-(5-amino-2-fluorobeazyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(2-amino-4-chloropyridin-6-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-amino-5-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-amino-3,5-difluorobenzyl)piperidine-4-n]-2-[(1R)-3,3-difluorocyclopentyl]-2-bihydroxy-2-phenylacetamide (2R)-N-[1-(benzimidazol-5-ylmeta)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclobutyl]-2-bihydroxy-2-phenylacetamide (2R)-N-[1-(6-Ammopyridin-2-ylmethyl)piperidin-4-yl]-2-(4,4-difluorocyclohexyl)-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-(4-fluorophenyl)-2-hydroxyacetamide 12. Compounds or their pharmaceutically acceptable salts according to Claim 1, characterized by the fact that in them the compound is represented by the general formula [I]: (2R)-N-[1-(6-methylpyridin-2-yl-methyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-thienylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-furylmethyl)piperidinyl-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2 hydroxy-2-phenylacetamide (2R)-N-[H2-furylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(2-pyridylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-methoxybenzyl)piperidin-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2 hydroxy-2-phenylacetamide (2R)-N-(1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenycetamide (2R)-N-[1-(3-fluorobenz)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-chlorobenzyl)piperidyl-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(2-thienylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-amino-4-methoxypyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-amino-5-methylbenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(2-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-aminobenza)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-amino-3-methoxybenzyl)piperidin-4-yl3-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3,5-diaminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(5-methylamino-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-methylbenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-bihydroxy-2-phenylacetamide (2R)-N-[1-(3-amino-5-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(4-amino-3-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-bihydroxy-2-phenylacetamide (2R)-N-[1-(6-amino-4-methylpyridin-2-yl)piperidu-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-amino-4-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(5-amino-2-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(2-amino-4-chloropyridin-6-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(3-amino-5-chlorobenal)piperidine-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2-lihydroxy-2-phenylacetamide (2R)-N-[1-(4-amino-3,5-difluorobenzyl)piperidine-4-a]-2-[(1R)-3,3-difluorocyclopentyl]-2-bihydroxy-2-phenylacetamide (2R)-N-[1-(benzimidazol-5-ylmethyl)piperidinyl-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-Ammopyridin-2-y]methyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclobutyl]-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-Ammopyrdin-2-ylmethyl)piperidin-4-yl]-2-(4,4-difluorocyclohexyl)-2-hydroxy-2-phenylacetamide (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-(4-fluorophenyl)-2-hydroxyacetamide . 13. A compound characterized in that it is (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2- hydroxy-2-phenylacetamide or a pharmaceutically acceptable salt thereof. 14. Pharmaceutical preparation, characterized in that it is prepared from the compound of the general formula [I] as presented in Claim 1 or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable adjuvant. 15. A pharmaceutical preparation as defined in Claim 13, characterized in that it is used in the treatment and prevention of diseases associated with muscarinic M3 receptors, for example such respiratory diseases as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable stomach syndrome, crampy colitis, diverticulitis and contraction of the smooth muscles of the digestive system accompanied by pain; urinary disorders such as urinary incontinence and frequency of neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, inconstant bladder, cystospasm and chronic cystitis; and motion sickness. 16. A method of treating or preventing diseases associated with muscarinic M3 receptors, for example such respiratory diseases as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable stomach syndrome, crampy colitis, diverticulitis and contraction of the smooth muscles of the digestive system accompanied by pain; urinary disorders such as urinary incontinence and frequency of neurogenic pollakiurea, neurogenic bladder, nocturnal enuresis, urinary incontinence, cystospasm and chronic cystitis; and motion sickness, characterized in that the compound of the general formula [I] as presented in Claim 1 or a pharmaceutically acceptable salt thereof is used. 17. The process for the preparation of 1,4-disubstituted piperidine derivatives containing fluorine of the general formula [I] as presented in Claim 1, characterized in that it comprises (a) reaction of a carboxylic acid of the general formula [III] [image] [where Ar has the same meaning as defined in Claim 1, and R10 represents C3-C6 cycloalkyl in which any of 1 to 4 hydrogen atoms may be substituted by a fluorine atom(s) or C3-C6 cycloalkyl having 1 to 2 protected or unprotected hydroxyl or oxo groups] or its reactive derivative with the compound of the general formula [IV] [image] [where R represents a C5-C15 saturated or unsaturated aliphatic hydrocarbon group in which any of 1 to 6 hydrogen atoms may be substituted with fluorine atom(s), a C5-C15 saturated or unsaturated aliphatic hydrocarbon group having 1-2 protected or unprotected a hydroxyl or oxo group, aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl group having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (optionally any of 1 to 3 hydrogen atoms on the ring in said aralkyl, arylalkenyl , heteroarylalkyl or heteroarylalkenyl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, unprotected or protected amino, unprotected or protected lower alkylamino or aralkyloxycarbonyl group) and X is NH or O]; and when R 10 or R 20 have unprotected or protected 1 to 2 hydroxyl or oxo group(s) converting said hydroxyl or oxo group(s) to fluorine atom(s) either as such or after removal of the protecting group(s); when R10 or R20 have protected amino or protected lower alkylamino group(s); and when R 10 or R 20 has lower alkoxycarbonyl or aralkyloxycarbonyl, converting the same to amino; or (b) by the reaction of a carboxylic acid of the above general formula [III] and its reactive derivative with a compound of the general formula [V] [image] [where E is a protecting group for an imino group and X is as defined above] or a salt thereof; by deprotection of the resulting compound of the general formula [VI] [image] [wherein Ar is as defined in Claim 1, R 10 , X and E are as defined above] thereafter by reacting the same with a compound of general formula [VII] R20-L [VII] [where L represents a leaving group and R20 is determined as above] in the presence of alkali if necessary, and again if necessary by conducting the conversion reaction of R10 and R20 similarly as above; or (c) deprotection of the compound of general formula [VI] above and subjecting it to reductive alkylation with a compound of general formula [VIII] R21-CHO [VIII] [where R21 represents a C4-C14 saturated or unsaturated aliphatic hydrocarbon group in which any of l to 6 hydrogen atoms may be substituted with fluorine atom(s), a C4-C14 saturated or unsaturated aliphatic hydrocarbon group having unprotected or protected l to 2 hydroxyl or oxo groups, aryl, aralkyl, arylalkenyl or heteroaryl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur (optionally any 1-3 ring hydrogen atoms in said aryl , aralkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, unprotected or protected amino, unprotected or protected lower alkylamino or aralkyloxycarbonyl)], and if is necessary by carrying out the conversion reaction of R10 and R21 downwardly towards the above. 18. A compound characterized in that it is (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid. 19. A compound characterized in that it is 64-tert-butyloxycarbonylaminopyridin-2-methanol, 6-tert-butyloxycarbonylaminopyridin-2-yl-methyl methanesulfonate, 6-tert-butyloxycarbonylaminopyridin-2-ylmethyl chloride or 6-tert-butyloxycarbonylaminopyridin-2-ylmethyl chloride. 2-ylmethyl bromide.